Geographical distance predicts psychiatric treatment retention for Hispanic women with comorbid major depression and breast cancer.

PURPOSE: Depression is among the most common comorbid psychiatric disorders of patients with breast cancer. Depression decreases patient quality of life and, if untreated, can adversely affect cancer treatment. We sought to identify treatment barriers for women with breast cancer receiving psychotherapy for depression. Findings may help policy makers and researchers determine funding and design of future studies involving this population, especially in communities with high rates of health disparities. METHODS: We used data from a randomized trial for women with breast cancer and current DSM-IV non-psychotic unipolar major depressive disorder (MDD). Patients were randomly assigned to 12 weeks of one of three psychotherapies and attrition was assessed by whether subjects completed 12 weekly treatment sessions. We used descriptive analyses and logistic regression to identify treatment barriers. R shiny was used to determine study patient residences. RESULTS: Of 134 randomized patients, 84 (62.7%) were Hispanic. Fifty-nine patients (44%) either did not start or dropped out of treatment, 49 (83.1%) of them being Hispanic. Being a Hispanic woman, less educated, and geographically distant from treatment significantly predicted attrition. Single Hispanic mothers had significantly higher attrition risk than married and/or childless women. CONCLUSION: Identifying barriers to treatment is important to improve treatment adherence for patients with concurrent diagnoses of breast cancer and MDD, especially for traditionally underserved minorities. Additional support such as affordable tele-medicine, multi-language assistance, financial aid for transportation and child-care, and allocation of more funds to address some identified barriers deserve consideration to improve treatment adherence and outcomes.

Statistical process control to monitor use of a web-based autoplanning tool.

PURPOSE: To investigate the use of statistical process control (SPC) for quality assurance of an integrated web-based autoplanning tool, Radiation Planning Assistant (RPA). METHODS: Automatically generated plans were downloaded and imported into two treatment planning systems (TPSs), RayStation and Eclipse, in which they were recalculated using fixed monitor units. The recalculated plans were then uploaded back to the RPA, and the mean dose differences for each contour between the original RPA and the TPSs plans were calculated. SPC was used to characterize the RPA plans in terms of two comparisons: RayStation TPS versus RPA and Eclipse TPS versus RPA for three anatomical sites, and variations in the machine parameters dosimetric leaf gap (DLG) and multileaf collimator transmission factor (MLC-TF) for two algorithms (Analytical Anisotropic Algorithm [AAA]) and Acuros in the Eclipse TPS. Overall, SPC was used to monitor the process of the RPA, while clinics would still perform their routine patient-specific QA. RESULTS: For RayStation, the average mean percent dose differences across all contours were 0.65% ± 1.05%, -2.09% ± 0.56%, and 0.28% ± 0.98% and average control limit ranges were 1.89% ± 1.32%, 2.16% ± 1.31%, and 2.65% ± 1.89% for the head and neck, cervix, and chest wall, respectively. In contrast, Eclipse's average mean percent dose differences across all contours were -0.62% ± 0.34%, 0.32% ± 0.23%, and -0.91% ± 0.98%, while average control limit ranges were 1.09% ± 0.77%, 3.69% ± 2.67%, 2.73% ± 1.86%, respectively. Averaging all contours and removing outliers, a 0% dose difference corresponded with a DLG value of 0.202 ± 0.019 cm and MLC-TF value of 0.020 ± 0.001 for Acuros and a DLG value of 0.135 ± 0.031 cm and MLC-TF value of 0.015 ± 0.001 for AAA. CONCLUSIONS: Differences in mean dose and control limits between RPA and two separately commissioned TPSs were determined. With varying control limits and means, SPC provides a flexible and useful process quality assurance tool for monitoring a complex automated system such as the RPA.

Angiopoietin 2 stimulates trophoblast invasion via a mechanism associated with JNK signaling.

Extravillous trophoblast cell (EVT) invasion is tightly controlled, and its dysregulation can lead to altered spiral artery remodeling and contribute to a number of different pregnancy complications. Angiopoietin-2 (Ang-2) is expressed by trophoblast cells and various cells in the decidua, and trophoblast cells express its receptor, Tie2. Ang-2 has been shown to play roles in tumor progression and metastasis but it is not known if it also regulates EVT invasion. Here, we show that both the HTR-8/SVneo cell line and primary isolates of human EVT expressed various integrins and the Tie2 receptor, and Ang-2 stimulated their migration and/or invasion. Ang-2 increased expression of matrix metalloproteinase (MMP)2 and MMP9, altered the cytoskeleton of HTR-8/SVneo cells and also induced phosphorylation of Tie2, JNK and c-Jun. Inhibition of p-JNK (using SP600125) blocked the Ang-2 induced invasion of HTR-8/SVneo cells. In addition, inhibition of Tie2 (pexmetinib) and integrin signaling (RGDS and ATN-161) also blocked Ang-2-induced invasion. In conclusion, we demonstrate that Ang-2 can stimulate EVT invasion via a mechanism associated with activation of both the Tie2 receptor and integrins, which appear to work through different pathways; Tie2 through the JNK/c-JUN pathway and integrins through an as yet unidentified pathway(s). We therefore propose that any alterations in Ang-2 expression in the decidua would lead to an imbalance in pro- and anti-invasive factors, disrupting regulation of EVT invasion and spiral artery remodeling and thereby contribute to the etiology of several complications of pregnancy.

T-cadherin inhibits invasion and migration of endometrial stromal cells in endometriosis.

STUDY QUESTION: What is the expression level of T-cadherin in endometriosis, and does T-cadherin play a role in regulating invasion and migration of endometrial stromal cells? SUMMARY ANSWER: T-cadherin expression was reduced in ectopic endometriotic lesions compared to eutopic endometrium, and T-cadherin overexpression inhibited the invasion and migration of endometrial stromal cells. WHAT IS KNOWN ALREADY: Endometriosis is a disease that involves active cell invasion and migration. T-cadherin can inhibit cell invasion, migration and proliferation in various cancer cells, but its role in endometriosis has not been investigated. STUDY DESIGN, SIZE, DURATION: We explored the expression status of T-cadherin in 40 patients with and 24 without endometriosis. We also isolated endometrial stromal cells to study the invasion, migration and signaling pathway regulation of T-cadherin overexpression. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were recruited at the Guangzhou Women and Children's Medical Center to study the expression levels of T-cadherin. The expression of T-cadherin was detected by immunohistochemistry staining and western blot. H-score was used to evaluate the staining intensity of T-cadherin. The correlation between T-cadherin expression levels (H-score) and endometriosis patients' age, stage, lesion size and adhesion was analyzed. Endometrial stromal cells from patients with and without endometriosis were isolated, and cell invasion and migration were detected by transwell assays after T-cadherin overexpression. The expression of vimentin in T-cadherin-overexpressed cells was detected by western blot. After T-cadherin overexpression, the phosphorylation profile of signaling pathway proteins was detected with the Proteome Profiler Human Phospho-Kinase Array Kit. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference in the expression of T-cadherin in the normal endometrium of control patients and the eutopic endometrium of endometriotic patients, but it was significantly decreased in the ectopic endometrium of endometriotic patients, compared with control endometrium and eutopic endometrium of endometriosis patients (P < 0.0001, for both). Western blot analysis also showed that the expression of T-cadherin was decreased in ectopic endometriotic lesions, but not the normal control endometrium or the endometriotic eutopic endometrium. The results of transwell assays indicated that T-cadherin overexpression inhibited the invasion and migration of endometrial stromal cells. In addition, T-cadherin overexpression promoted the phosphorylation of HSP27 (S78/S82) and JNK 1/2/3 (T183/Y185, T221/Y223) and decreased the expression of vimentin, MMP2 and MMP9 in eutopic endometriosis stromal cells. LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The control group were patients with benign gynecological conditions (e.g. uterus myoma, endometrial or cervical polyp), which may have genetic or epigenetic variations associated with T-cadherin expression and signaling pathways. The case numbers of involved endometriosis and control patients were limited. This study only used endometrial stromal cells from patients with or without endometriosis. Ideally, ectopic endometrial stromal cells of the ovarian endometriotic lesions should also be utilized to explore the function of T-cadherin. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation of the role of T-cadherin in endometriosis may generate new potential therapeutic targets for this complex disorder. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by the Natural Science Foundation of Guangdong Province (2016A030313495), National Natural Science Foundation of China (81702567, 81671406, 31871412), the Science and Technology Programs of Guangdong (2017A050501021), Medical Science Technology Research Fund of Guangdong Province (A2018075), the Science and Technology Programs of Guangzhou City (201704030103), Internal Project of Family Planning Research Institute of Guangdong Province (S2018004), Post-doc initiation fund of Guangzhou (3302) and Post-doc science research initiation fund of Guangzhou Women and Children's Medical Center (20160322). There are no conflicts of interest.

Serum 25 hydroxyvitamin D status in 6-month-old infants in Guangzhou, China: A paired longitudinal follow up study.

To assess the vitamin D status in healthy 6-month-old infants, as well as vitamin D supplementation and feeding patterns in Guangzhou, China, serum 25-hydroxyvitamin D (25OHD) concentrations of 202 infants were measured at birth (cord blood) and at 6 months of age in Guangzhou, China. Questionnaires acquiring demographic characteristics, maternal and infantile vitamin D supplementation during pregnancy and first 6 months after birth, and feeding patterns during the first 6 months were completed by participating mothers. Physical examinations and blood sampling were carried out among infants at 6 months of age. The majority of infants (93.6%) were supplemented with vitamin D during the first 6 months of life on a voluntary basis. The M ± SD of cord serum 25OHD concentration was 46.2 ± 16.4 nmol/L, whereas the M ± SD of 25OHD concentration at 6 months was 82.9 ± 24.9 nmol/L. Serum 25OHD concentrations <30 nmol/L were seen in 34 (16.8%) infants at birth but only one (0.5%) at 6 months. Only 11 (5.4%) infants had concentrations >75 nmol/L at birth, whereas the majority of infants (n = 131, 64.9%) had concentrations >75 nmol/L at 6 months. The main predictors of 25OHD levels at 6 months included season, vitamin D supplementation, parental education level, and feeding patterns. To conclude, serum 25OHD concentrations were low at birth in a southern Chinese population, and infantile supplementation is an effective way to improve 25OHD status. Exclusively breastfed infants might need greater vitamin D supplementation, and individualized vitamin D supplementation plans might be needed.

Cord serum vitamin D in a South China birth cohort.

BACKGROUND AND OBJECTIVES: Vitamin D deficiency during pregnancy has been associated with many adverse pregnancy and birth outcomes. Low serum 25-hydroxyvitamin D (25OHD) levels (<30 nmol/L) increases the risk of nutritional rickets. This study aimed to investigate the concentration of cord serum 25OHD in a birth cohort in Guangzhou, China and determine whether maternal lifestyle factors had any effect on these levels. METHODS AND STUDY DESIGN: A total of 854 pregnant women giving birth between Dec 2016 and Dec 2017 were recruited to this study. Basic information was obtained from the clinical database. A voluntary retrospective pregnancy lifestyle questionnaire was completed by 388 participants. The concentration of serum 25OHD, calcium, phosphorus, and alkaline phosphatase (ALP) were measured in umbilical cord blood. RESULTS: The mean (SD) of cord serum 25OHD was 44.7 (16.7) nmol/L. The prevalence of cord 25OHD <30 nmol/L was 22.2% and 70.4% had levels <50 nmol/L. The prevalence of vitamin D deficiency is higher in infants born in winter months (31% <30 nmol/L and 76% <50 nmol/L), compared to those born in the summer (12% <30 nmol/L and 64% <50 nmol/L). Infants born to women taking a vitamin D containing supplement had approximately 10 nmol/L higher levels of 25OHD than those who did not supplement their diets. CONCLUSIONS: Summer born infants have higher serum 25OHD levels at birth, but there are still infants being born with vitamin D deficiency. Vitamin D containing supplement use during pregnancy was effective in raising cord serum vitamin D levels.

How to Be Modern? The Social Negotiation of 'Good Food' in Contemporary China.

Developing safe and sustainable food production for its population has been central to China's 'Modernisation Project'. Yet recent fieldwork in three Chinese cities suggests that there are two conflicting views on what a 'modern' agriculture should look like. For the government, modernisation implies a rational calculation of scale and a mirroring of global trends. But an alternative interpretation of modernity, promoted by civil society, has been gaining ground. For this camp, good food production is then established through a 'rhizomic' spread of new practices, which are inspired by world possibilities but are deeply rooted in the local context. Based on 14 interviews and five focus groups, this article investigates the ongoing social negotiation of 'good food' in China. It demonstrates how a non-western society responds to the twin processes of modernisation and globalisation and provides insights on the varieties of modernity in the making.

Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer.

There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Impact of pregnancy on vitamin D status: a longitudinal study.

Nutritional requirements for vitamin D during pregnancy have been inadequately described, and there are conflicting data on the impact of gestation on vitamin D status. In the present study, we conducted a longitudinal analysis of total and free (unbound) serum 25-hydroxyvitamin D (25(OH)D), vitamin D-binding protein (DBP) and albumin concentrations in a random sample of thirty women from the Screening for Pregnancy Endpoints Ireland pregnancy cohort study at 15, 20, 24, 28, 32, 36 and 40 weeks of gestation and at 2 months postpartum. Concentrations of serum 25(OH)D, DBP and albumin were determined, and free 25(OH)D was calculated from the concentrations of total 25(OH)D, DBP and albumin. Serum albumin concentration decreased during pregnancy (P< 0·001), with a nadir at 36 weeks (P< 0·005), during which the concentration was approximately 80 % of the postnatal concentration. Serum DBP concentration increased during pregnancy and at 28 weeks of gestation, which was almost double the postnatal level (P< 0·001). Total and free 25(OH)D concentrations decreased (both P< 0·005) as pregnancy progressed, and both were lowest at 36 weeks of gestation. At 15 weeks, 10 and 63 % of the women had serum 25(OH)D concentration < 30 and 50 nmol/l, respectively, which increased to 53 and 80 % at 36 weeks of gestation. The time course of decreasing concentrations of 25(OH)D during gestation among women recruited during May-July, who delivered between October and November, and among those recruited in August-September, who delivered between February and March, was similar. The lower percentage of free 25(OH)D during pregnancy is mainly due to increased DBP.

Dispensaries and Medical Marijuana Certifications and Indications: Unveiling the Geographic Connections in Pennsylvania, USA.

Introduction: Pennsylvania opened its first medical marijuana (MMJ) dispensary in 2018. Qualifying conditions include six conditions determined to have no or insufficient evidence to support or refute MMJ effectiveness. We conducted a study to describe MMJ dispensary access in Pennsylvania and to determine whether dispensary proximity was associated with MMJ certifications and community demographics. Methods: Using data from the Pennsylvania Department of Health, we geocoded MMJ dispensary locations and linked them to US Census Bureau data. We created dispensary access measures from the population-weighted centroid of Zip Code Tabulation Areas (ZCTAs): distance to nearest dispensary and density of dispensaries within a 15-min drive. We evaluated associations between dispensary access and the proportion of adults who received MMJ certification and the proportion of certifications for low evidence conditions (amyotrophic lateral sclerosis, epilepsy, glaucoma, Huntington's disease, opioid use disorder, and Parkinson's disease) using negative binomial modeling, adjusting for community features. To evaluate associations racial and ethnic composition of communities and distance to nearest dispensary, we used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for median income. Results: Distance and density of MMJ dispensaries were associated with the proportion of the ZCTA population certified and the proportion of certifications for insufficient evidence conditions. Compared to ZCTAs with no dispensary within 15 min, the proportion of adults certified increased by up to 31% and the proportion of certifications for insufficient evidence decreased by up to 22% for ZCTAs with two dispensaries. From 2018 to 2021, the odds of being within five miles of a dispensary was up to 20 times higher in ZCTAs with the highest proportions of individuals who were not White (2019: OR: 20.14, CI: 10.7-37.8) and more than double in ZCTAs with the highest proportion of Hispanic individuals (2018: OR: 2.81, CI: 1.51-5.24), compared to ZCTAs with the lowest proportions. Conclusions: Greater dispensary access was associated with the proportions of certified residents and certifications for low evidence conditions. Whether these patterns are due to differences in accessibility or demand is unknown. Associations between community demographics and dispensary proximity may indicate MMJ access differences.

Interleukin-1 beta signals through the ERK signalling pathway to modulate human placental trophoblast migration and invasion in the first trimester of pregnancy.

INTRODUCTION: Interleukin-1 beta (IL-1ß) can promote cell migration, invasion and metastasis in various cancer cells. The mechanism of its role in human trophoblast has not been fully investigated. Therefore, we aimed to investigate the expression level of IL-1ß in first trimester decidua and placenta and its potential role in regulation of extravillous trophoblast cell (EVT) invasion and migration. METHODS: First trimester placenta and decidua were collected to study the expression levels of IL-1ß and its receptors by immunohistochemical staining. Primary isolates of first trimester EVT or the HTR-8/SVneo trophoblast like cell line were used to assess migration and invasion. Matrix metalloproteinase levels were assessed by gelatin zymography and ELISA. The phosphorylation profile of signaling pathway proteins was detected with the Proteome Profiler Human Phospho-Kinase Array Kit. Differentially expressed proteins in cells was detected and verified by Western Blot. RESULTS: IL-1ß, its receptors and antagonist are expressed in first trimester placenta and decidua, exogenous IL-1ß stimulates trophoblast cell outgrowth, migration and invasion through the ERK signaling pathway. IL-1ß was significantly increased in the placenta at 6-7 weeks gestation compared with 8-9 weeks gestation (P < 0.0001). Transwell and RTCA assays indicated that IL-1ß stimulates the invasion and migration of EVT. In addition, IL-1ß promoted the phosphorylation of ERK 1/2. It also promoted the expression of MMP2 and MMP9 in EVT as demonstrated by gelatin zymography assay and enzyme linked immunosorbent assay. DISCUSSION: This study demonstrated IL-1ß expression in placenta and decidua, and that it regulates EVT invasion and migration.

Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.

A technique to use CT images for in vivo detection and quantification of the spatial distribution of radiation-induced esophagitis.

The purpose of the study was to examine whether CT imaging can be used to quantify radiation-induced injury to the esophagus. Weekly CT images for 14 patients receiving proton therapy for thoracic tumors were retrospectively reviewed. The images were registered with the original treatment planning CT image using deformable registration techniques, and the esophageal contours from the treatment plan were automatically mapped to the weekly images. The relative change in the size of the esophagus was calculated for each CT slice as the ratio of the cross-sectional area of the esophagus (minus air) in the weekly CT image to the same area in the planning CT image. The maximum relative change in cross sectional area for each CT image was calculated and examined for correlation with the clinical toxicity score for all the patients. The average maximum relative expansion of the esophagus at the end of treatment was 1.41 ± 0.26, 1.68 ± 0.36, and 2.10 ± 0.18 for patients with grade 0, 2, and 3 esophagitis, respectively. An unpaired t-test, with the level of significance corrected with a Bonferroni correction, showed that the difference between grade 3 and 0 was significant, but the differences between grade 0 and 2, and 2 and 3 were not. The timing of changes in esophageal expansion closely matched that of clinically noted changes in patient symptoms. Expansion of the esophagus on CT images has potential as an objective measure of toxicity. The ability to quantify objectively the spatial distribution of radiation-induced injury will be a useful tool in understanding the impact of partial esophageal sparing on the probability of esophagitis.

Commoning genomic solidarity to improve global health equality.

This article underlines two key asynchronies between prevailing governing logic and expanding practices in somatic human genome editing that are hindering an effective and orderly translation of the new technology into public good. The first is a "genomic sovereignty" framing adopted by a number of non-Western countries that may exacerbate data biases in global research and that directs policy attention away from the necessary structural changes required to achieve non-discriminatory and equitable genomic healthcare. The other is a global deficiency in attending to "science at large": the challenge of regulating new assemblages of societal interests that advocate controversial or experimental research, often outside of conventional institutions and aided by "policy shopping." Both issues point to the fact that genomic research does not represent a well-defined scientific commons but rather a domain that requires active "commoning," with the aim of fostering genomic solidarity that coordinates responsible research within and across national boundaries.

Hepatotoxicity from high-dose methotrexate in primary central nervous system lymphoma.

Background: High-dose methotrexate (HDMTX) is a mainstay of primary central nervous system lymphoma (PCNSL) treatment. Transient hepatotoxicity from HDMTX has been characterized in pediatric patients but not in adults. We sought to characterize hepatotoxicity in adult PCNSL patients undergoing HDMTX treatment. Methods: Retrospective study of 65 PCNSL patients treated at the University of Virginia from 02/01/2002 to 04/01/2020 was performed. Hepatotoxicity was defined using National Cancer Institute Common Toxicity Criteria (CTC) for adverse events, fifth version. High-grade hepatotoxicity was defined as a bilirubin or aminotransferase CTC grade of 3 or 4. Relationships between clinical factors and hepatotoxicity were assessed with logistic regression. Results: Most patients (90.8%) had a rise of at least one aminotransferase CTC grade during HDMTX treatment. 46.2% had high-grade hepatotoxicity based on aminotransferase CTC grade. No patients developed high-grade bilirubin CTC grades during chemotherapy. Liver enzyme test values decreased to low CTC grade or normal in 93.8% of patients after the conclusion of HDMTX treatment without treatment regimen changes. Prior ALT elevation (P = .0120) was a statistically significant predictor of high-grade hepatotoxicity during treatment. Prior history of hypertension was associated with increased risk of toxic serum methotrexate levels during any cycle (P = .0036). Conclusions: Hepatotoxicity develops in the majority of HDMTX-treated PCNSL patients. Transaminase values decreased to low or normal CTC grades in almost all patients after treatment, without modification of MTX dosage. Prior ALT elevation may predict patients' increased hepatotoxicity risk, and hypertension history may be a risk factor for delayed MTX excretion.

Astrocytic junctional adhesion molecule-A regulates T-cell entry past the glia limitans to promote central nervous system autoimmune attack.

Contact-mediated interactions between the astrocytic endfeet and infiltrating immune cells within the perivascular space are underexplored, yet represent potential regulatory check-points against CNS autoimmune disease and disability. Reactive astrocytes upregulate junctional adhesion molecule-A, an immunoglobulin-like cell surface receptor that binds to T cells via its ligand, the integrin, lymphocyte function-associated antigen-1. Here, we tested the role of astrocytic junctional adhesion molecule-A in regulating CNS autoinflammatory disease. In cell co-cultures, we found that junctional adhesion molecule-A-mediated signalling between astrocytes and T cells increases levels of matrix metalloproteinase-2, C-C motif chemokine ligand 2 and granulocyte-macrophage colony-stimulating factor, pro-inflammatory factors driving lymphocyte entry and pathogenicity in multiple sclerosis and experimental autoimmune encephalomyelitis, an animal model of CNS autoimmune disease. In experimental autoimmune encephalomyelitis, mice with astrocyte-specific JAM-A deletion (mGFAP:CreJAM-Afl/fl ) exhibit decreased levels of matrix metalloproteinase-2, reduced ability of T cells to infiltrate the CNS parenchyma from the perivascular spaces and a milder histopathological and clinical course of disease compared with wild-type controls (JAM-Afl/fl ). Treatment of wild-type mice with intraperitoneal injection of soluble junctional adhesion molecule-A blocking peptide decreases the severity of experimental autoimmune encephalomyelitis, highlighting the potential of contact-mediated astrocyte-immune cell signalling as a novel translational target against neuroinflammatory disease.

To Procrastinate or Not to Procrastinate: A Retrospective Study of the Optimal Timing of Containing the Global Spread of the COVID-19 Pandemic.

As global public health is under threat by the 2019-nCoV and a potential new wave of large-scale epidemic outbreak and spread is looming, an imminent question to ask is what the optimal strategy of epidemic prevention and control (P&C) measures would be, especially in terms of the timing of enforcing aggressive policy response so as to maximize health efficacy and to contain pandemic spread. Based on the current global pandemic statistic data, here we developed a logistic probability function configured SEIR model to analyse the COVID-19 outbreak and estimate its transmission pattern under different "anticipate- or delay-to-activate" policy response scenarios in containing the pandemic. We found that the potential positive effects of stringent pandemic P&C measures would be almost canceled out in case of significantly delayed action, whereas a partially procrastinatory wait-and-see control policy may still be able to contribute to containing the degree of epidemic spread although its effectiveness may be significantly compromised compared to a scenario of early intervention coupled with stringent P&C measures. A laissez-faire policy adopted by the government and health authority to tackling the uncertainly of COVID19-type pandemic development during the early stage of the outbreak turns out to be a high risk strategy from optimal control perspective, as significant damages would be produced as a consequence.

The Cosmopolitanization of Science: Experience from Chinese Stem Cell Scientists.

It is commonly perceived that the 'globalization of science' may result in a 'Westernization of science'. In this paper, however, I use the case of stem cell science in China to demonstrate that developing countries are sometimes able to effectively shape the norms of global/local scientific exchange. Based on interviews with 38 stem cell scientists in six Chinese cities in early 2008, this paper elucidates Chinese scientists' outlook towards cross-border collaborations and the effects that the internationalization of science has had on everyday laboratory operations. Findings suggest that although there still exists an asymmetry of scientific influence, and in many aspects China is still 'catching-up' to the West, there is also a changing nature of communication beyond borders. One key aspect of recent international scientific development is the growing necessity for local stakeholders to acquire a global mindset and to compare, reflect and accommodate diverse interests. This is what I define as the 'cosmopolitanization of science'. The study empirically examines the sociological and methodological implications of the cosmopolitanization process and further develops Ulrich Beck's cosmopolitan theory by delineating four main features of the 'cosmopolitanization of science': shared future benefits, passive ethicization, reflexive negotiation, and continuous performance.