Potentially Inappropriate Medication Use in Older Adults With Multimorbidity in Taiwan.

BACKGROUND: Medication-related problem is a concerning issue in older adults with multimorbidity due to complexity of disease conditions and polypharmacy, and may lead to increase in risk for adverse health outcomes. This study aims to investigate the prevalence and associated factors of potentially inappropriate medication use among the growing population of older adults with multimorbidity in Taiwan. METHOD: The study population was composed of patients who were aged 65 years or older with multimorbidity (two or more chronic diseases) and had at least one outpatient clinic visit with drug prescription in 2018 identified from the Taiwan National Health Insurance Research Database. Potentially inappropriate medication use was defined using the 2019 Beers criteria for drugs to be avoided for older adults. Multiple logistic regression model was conducted to examine patient-related and prescriber-related factors associated with PIM use. RESULTS: A total of 2 432 416 patients (69.7% of the entire older adult population) had multimorbidity and received at least one drug prescription at the outpatient clinic in Taiwan in 2018. The prevalence of having at least one PIM in this population was found to be 85.6%. Patient-related factors (age, sex, specific chronic diseases, frequency of outpatient visits) and prescriber-related factors (physician characteristics, healthcare setting, total number of medications, prior PIM use) were found to be associated with use of PIM. CONCLUSION: High prevalence of PIM use was found in older patients with multimorbidity in Taiwan. Both patient-related and prescriber-related factors had been found to be predictors of PIM use, and should be addressed when trying to improve the medication quality in this population.

Association Between Premorbid Metabolic Syndrome and Coronary Arterial Stenosis: Results from One Medical Center in Taiwan.

Background: Although the relationship between metabolic syndrome (MetS) and cardiovascular disease is already well-established, there is limited evidence as to whether individuals are at risk for cardiovascular disease during the premorbid state of MetS. The aim of this study is to explore the relationship between coronary arterial stenosis and MetS in a nonhypertensive and nondiabetic population. Methods: In this cross-sectional study, we analyzed the data of participants who underwent annual health checkups in a medical center. These data were collected from physical examination, blood tests, cardiac computed tomography examinations, and medical charts. We excluded those with established hypertension or diabetes and age of <50 or >75 years. Results: This study recruited 700 participants with a mean age of 59.5 years. More than 31% had MetS, and the overall prevalence of coronary arterial stenosis was 48.0% (grade 1, 2, 3, 4: 16.3%, 20.9%, 8.4%, 2.4%, respectively). In univariate analysis, older age, male sex, smoking, body mass index, elevated fasting plasma glucose (FPG), elevated triglyceride, lower level of high-density lipoprotein cholesterol, and presence of MetS were all positively correlated with coronary arterial stenosis. After adjustment for confounding factors, MetS still showed strong association with high grades of coronary arterial stenosis [odds ratio (OR) 2.86, confidence interval (95% CI) 1.30-4.01]. Specific components of MetS, such as elevated triglyceride [OR 2.02, 95% CI 1.14-3.57] and elevated FPG [OR 2.25, 95% CI 1.31-3.88], were also associated with coronary arterial stenosis. Conclusion: Our study concluded that premorbid MetS was significantly associated with coronary arterial stenosis. As for the individual components, elevated triglyceride and elevated FPG were both correlated with coronary arterial stenosis. Early preventive measures would be suggested at this stage of MetS to prevent future cardiovascular events.

Robotic inguinal hernia repair: is the new Da Vinci single port platform providing any benefit?

BACKGROUND: The utilization of the robot for inguinal hernia repairs has increased in the past years. The new Da Vinci Single Port (SP) system provides the benefits of single-incision procedures and might overcome the technical difficulties of previous single-incision techniques. The aim of this study was to evaluate the safety and feasibility of the SP transabdominal preperitoneal inguinal hernia repair (SP-TAPP) and compare its outcomes to the robotic multiport technique (MP-TAPP). METHODS: A prospective cohort of patients who underwent a robotic SP-TAPP and MP-TAPP between 2012 and 2022 was analyzed. Primary endpoints were same-day discharge, morbidity, and inguinal recurrence rates. Secondary endpoints included conversion, operative time, port-site incisional hernia, and chronic pain. RESULTS: MP-TAPP and SP-TAPP were performed in 378 (81.3%) and 87 (18.7%) patients, respectively. Demographics were similar between groups. There were no conversions or intraoperative complications. Mean operative (MP-TAPP: 93.2 vs. SP-TAPP: 78.1 min, p = 0.003) and recovery time (MP-TAPP: 160.8 vs SP-TAPP: 112.6 min, p < 0.001) were significantly shorter in the SP group. Same-day discharge rate was higher (MP-TAPP: 86.5% vs. SP-TAPP: 97.7%, p = 0.001) after SP-TAPP; 30-day morbidity, readmissions, and chronic pain rates were similar between groups. After a mean follow-up of 30.6 months for MP-TAPP and 13.3 months for SP-TAPP, inguinal hernia recurrence and port-site incisional rates were similar between groups. CONCLUSION: Robotic SP-TAPP is safe and feasible. When compared to MP-TAPP, it showed similar postoperative morbidity, higher same-day discharge rates, and a quicker postoperative recovery. Further studies are needed to confirm the benefits of the SP platform.

Robotic single-port surgery: Preliminary experience in general surgery.

BACKGROUND: We aim to analyse the safety and feasibility of the DaVinci Single Port (SP) platform in general surgery. METHODS: A prospective series of robotic SP transabdominal pre-peritoneal inguinal hernia repairs (SP-TAPP) and cholecystectomies (SP-C) (off-label) were analysed. Primary endpoints were safety and feasibility defined by the need for conversion and incidence of perioperative complications. RESULTS: A total of 225 SP procedures were performed; 84 (37.3%) SP-TAPP (70 unilateral, 7 bilateral), and 141 (62.7%) SP-C. There were no conversions or additional ports placed. Mean console time was 17.6, 31.9, and 54 min for SP-C, unilateral, and bilateral SP-TAPP, respectively. There was no mortality, intraoperative or major postoperative complications. Mean LOS was 2.7 h for elective SP-TAPP and 2.3 h for SP-C. CONCLUSION: Robotic SP surgery is safe and feasible for two of the most performed general surgery operations. Further experience might allow expanding the applications of robotic single-incision surgery for other procedures.

Ligand-independent integrin ß1 signaling supports lung adenocarcinoma development.

Integrins - the principal extracellular matrix (ECM) receptors of the cell - promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin ß1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin ß1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin ß1-mediated adhesion to ECM but are dependent on integrin ß1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). These studies support a critical role for integrin ß1 in lung tumorigenesis that is mediated through constitutive, ECM binding-independent signaling involving the cytoplasmic tail.

Longitudinal Remote SBRT/SRS Training in Latin America: A Prospective Cohort Study.

Background: Continuing medical education in stereotactic technology are scarcely accessible in developing countries. We report the results of upscaling a longitudinal telehealth training course on stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS), after successfully developing a pilot course in Latin America. Methods: Longitudinal training on SBRT and SRS was provided to radiation oncology practitioners in Peru and Colombia at no cost. The program included sixteen weekly 1-hour live conferencing sessions with interactive didactics and a cloud-based platform for case-based learning. Participant-reported confidence was measured in 16 SBRT/SRS practical domains, based on a 1-to-5 Likert scale. Pre- and post-curriculum exams were required for participation credit. Knowledge-baseline, pre- and post-curriculum surveys, overall and single professional-group confidence changes, and exam results were assessed. Results: One hundred and seventy-three radiotherapy professionals participated. An average of 56 (SD ±18) attendees per session were registered. Fifty (29.7%) participants completed the pre- and post-curriculum surveys, of which 30% were radiation oncologists (RO), 26% radiation therapists (RTT), 20% residents, 18% medical physicists and 6% neurosurgeons. Significant improvements were found across all 16 domains with overall mean +0.55 (SD ±0.17, p<0.001) Likert-scale points. Significant improvements in individual competences were most common among medical physicists, RTT and residents. Pre- and post-curriculum exams yielded a mean 16.15/30 (53.8 ± 20.3%) and 23.6/30 (78.7 ± 19.3%) correct answers (p<0.001). Conclusion: Longitudinal telehealth training is an effective method for improving confidence and knowledge on SBRT/SRS amongst professionals. Remote continuing medical education should be widely adopted in lower-middle income countries.

Robotic Surgery: Rediscovering Human Anatomy.

Since its advent, robotic surgery has redefined the operating room experience. It directly addressed and resolved many of the shortcomings of laparoscopic methods while maintaining a minimally invasive approach that brought benefits in cosmesis and healing for patients but also benefits in ergonomics and precision for surgeons. This new platform has brought with it changes in surgical training and education, principally through the utilization of virtual reality. Accurate depictions of human anatomy seen through augmented reality allow the surgeon-in-training to learn, practice and perfect their skills before they operate on their first patient. However, the anatomical knowledge required for minimally invasive surgery (MIS) is distinct from current methods of dissection and prosection that inherently cater towards open surgery with large cuts and unobstructed field. It is integral that robotic surgeons are also equipped with accurate anatomical information, heralding a new era in which anatomists can work alongside those developing virtual reality technology to create anatomical training curricula for MIS. As the field of surgery and medicine in general moves to include more and more technology, it is only fitting that the building blocks of medical education follow suit and rediscover human anatomy in a modern context.

Development of Machine Learning Models for Prediction of Smoking Cessation Outcome.

Predictors for success in smoking cessation have been studied, but a prediction model capable of providing a success rate for each patient attempting to quit smoking is still lacking. The aim of this study is to develop prediction models using machine learning algorithms to predict the outcome of smoking cessation. Data was acquired from patients underwent smoking cessation program at one medical center in Northern Taiwan. A total of 4875 enrollments fulfilled our inclusion criteria. Models with artificial neural network (ANN), support vector machine (SVM), random forest (RF), logistic regression (LoR), k-nearest neighbor (KNN), classification and regression tree (CART), and naïve Bayes (NB) were trained to predict the final smoking status of the patients in a six-month period. Sensitivity, specificity, accuracy, and area under receiver operating characteristic (ROC) curve (AUC or ROC value) were used to determine the performance of the models. We adopted the ANN model which reached a slightly better performance, with a sensitivity of 0.704, a specificity of 0.567, an accuracy of 0.640, and an ROC value of 0.660 (95% confidence interval (CI): 0.617-0.702) for prediction in smoking cessation outcome. A predictive model for smoking cessation was constructed. The model could aid in providing the predicted success rate for all smokers. It also had the potential to achieve personalized and precision medicine for treatment of smoking cessation.

Cannabinoid type 1 receptors in A2a neurons contribute to cocaine-environment association.

RATIONALE: Cannabinoid type 1 receptors (CB1Rs) are widely expressed within the brain's reward circuits and are implicated in regulating drug induced behavioral adaptations. Understanding how CB1R signaling in discrete circuits and cell types contributes to drug-related behavior provides further insight into the pathology of substance use disorders. OBJECTIVE AND METHODS: We sought to determine how cell type-specific expression of CB1Rs within striatal circuits contributes to cocaine-induced behavioral plasticity, hypothesizing that CB1R function in distinct striatal neuron populations would differentially impact behavioral outcomes. We crossed conditional Cnr1fl/fl mice and striatal output pathway cre lines (Drd1a -cre; D1, Adora2a -cre; A2a) to generate cell type-specific CB1R knockout mice and assessed their performance in cocaine locomotor and associative behavioral assays. RESULTS: Both knockout lines retained typical locomotor activity at baseline. D1-Cre x Cnr1fl/fl mice did not display hyperlocomotion in response to acute cocaine dosing, and both knockout lines exhibited blunted locomotor activity across repeated cocaine doses. A2a-cre Cnr1fl/fl, mice did not express a preference for cocaine paired environments in a two-choice place preference task. CONCLUSIONS: This study aids in mapping CB1R-dependent cocaine-induced behavioral adaptations onto distinct striatal neuron subtypes. A reduction of cocaine-induced locomotor activation in the D1- and A2a-Cnr1 knockout mice supports a role for CB1R function in the motor circuit. Furthermore, a lack of preference for cocaine-associated context in A2a-Cnr1 mice suggests that CB1Rs on A2a-neuron inhibitory terminals are necessary for either reward perception, memory consolidation, or recall. These results direct future investigations into CB1R-dependent adaptations underlying the development and persistence of substance use disorders.

Leveraging Telehealth and Medical Student Volunteers to Bridge Gaps in Education Access for Providers in Limited-Resource Settings.

PROBLEM: High-quality training opportunities for providers in limited-resource settings are often scarce or nonexistent. This can lead to a dearth of boots-on-the-ground workers capable of translating knowledge into effective action. The tested telehealth education model of Project ECHO (Extension for Community Healthcare Outcomes) can help address this disparity. However, the planning and logistical coordination required can be limiting. APPROACH: Medical student volunteers interested in health disparities and global health can be leveraged to reduce the costs of administration for Project ECHO programs. From mid-2018 to present (2020), student organizations have been formed at Vanderbilt University School of Medicine, University of California, San Francisco, School of Medicine, and Albert Einstein College of Medicine. These organizations have recruited and trained volunteers, who play an active role in assessing the needs of local clinics and providers, developing curricula, and coordinating the logistical aspects of programs. OUTCOMES: In the first 4 student-coordinated Project ECHO cohorts (2019-2020), 25 clinics in 14 countries participated, with a potential impact on over 20,000 cancer patients annually. Satisfaction with the telehealth education programs was high among local clinicians and expert educators. Students' perceived ability to conduct activities important to successfully orchestrating a telehealth education program was significantly greater among students who had coordinated one or more Project ECHO programs than among students who had yet to participate for 7 of 9 competencies. There also appears to be an additive effect of participating in additional Project ECHO programs on perceived confidence and career path intentions. NEXT STEPS: The student-led model of coordinating telehealth education programs described here can be readily expanded to medical schools across the nation and beyond. With continued expansion, efforts are needed to develop assessments that provide insights into participants' learning, track changes in patient outcomes, and provide continuing medical education credits to local clinicians.

Impact of High-Dose-Rate Brachytherapy Training via Telehealth in Low- and Middle-Income Countries.

PURPOSE: Our objective was to demonstrate the efficacy of a telehealth training course on high-dose-rate (HDR) brachytherapy for gynecologic cancer treatment for clinicians in low- and middle-income countries (LMICs). METHODS: A 12-week course consisting of 16 live video sessions was offered to 10 cancer centers in the Middle East, Africa, and Nepal. A total of 46 participants joined the course, and 22 participants, on average, attended each session. Radiation oncologists and medical physicists from 11 US and international institutions prepared and provided lectures for each topic covered in the course. Confidence surveys of 15 practical competencies were administered to participants before and after the course. Competencies focused on HDR commissioning, shielding, treatment planning, radiobiology, and applicators. Pre- and post-program surveys of provider confidence, measured by 5-point Likert scale, were administered and compared. RESULTS: Forty-six participants, including seven chief medical physicists, 16 senior medical physicists, five radiation oncologists, and three dosimetrists, representing nine countries attended education sessions. Reported confidence scores, both aggregate and paired, demonstrated increases in confidence in all 15 competencies. Post-curriculum score improvement was statistically significant (P < .05) for paired respondents in 11 of 15 domains. Absolute improvements were largest for confidence in applicator commissioning (2.3 to 3.8, P = .009), treatment planning system commissioning (2.2 to 3.9, P = .0055), and commissioning an HDR machine (2.2 to 4.0, P = .0031). Overall confidence in providing HDR brachytherapy services safely and teaching other providers increased from 3.1 to 3.8 and 3.0 to 3.5, respectively. CONCLUSION: A 12-week, low-cost telehealth training program on HDR brachytherapy improved confidence in treatment delivery and teaching for clinicians in 10 participating LMICs.

Effects of ibrutinib on in vitro platelet aggregation in blood samples from healthy donors and donors with platelet dysfunction.

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK), is approved in the US and EU for the treatment of various B-cell malignancies. In clinical studies, BTK inhibitors have been associated with increased bleeding risk, which may result from BTK inhibition in platelets.Methods: To better understand the mechanism of ibrutinib in bleeding events, we isolated platelet-rich plasma from healthy donors (n = 8) and donors with conditions associated with impaired platelet function or with potentially increased bleeding risk (on hemodialysis, taking aspirin, or taking warfarin; n = 8 each cohort) and used light transmission aggregometry to assess platelet aggregation in vitro after exposure to escalating concentrations of ibrutinib, spanning and exceeding the pharmacologic range of clinical exposure.Results: Platelet aggregation was induced by agonists of 5 major platelet receptors: adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP6), ristocetin, collagen, or arachidonic acid (AA). Platelet aggregation induced by ADP, TRAP6, ristocetin, and AA was not meaningfully inhibited by the maximal concentrations of ibrutinib (10 µM). In contrast, collagen-induced platelet aggregation was dose-dependently inhibited by ibrutinib in all donor cohorts (maximum aggregation % with 10 µM ibrutinib, -64% to -83% of agonist activity compared to control agonist samples but without ibrutinib).Conclusion: These results confirm prior reports and support a mechanistic role for the inhibition of collagen-induced platelet aggregation in bleeding events among susceptible individuals receiving ibrutinib therapy.

LncRNA H19 Suppresses Osteosarcomagenesis by Regulating snoRNAs and DNA Repair Protein Complexes.

Osteosarcoma is one of the most frequent common primary malignant tumors in childhood and adolescence. Long non-coding RNAs (lncRNAs) have been reported to regulate the initiation and progression of tumors. However, the exact molecular mechanisms involving lncRNA in osteosarcomagenesis remain largely unknown. Li-Fraumeni syndrome (LFS) is a familial cancer syndrome caused by germline p53 mutation. We investigated the tumor suppressor function of lncRNA H19 in LFS-associated osteosarcoma. Analyzing H19-induced transcriptome alterations in LFS induced pluripotent stem cell (iPSC)-derived osteoblasts, we unexpectedly discovered a large group of snoRNAs whose expression was significantly affected by H19. We identified SNORA7A among the H19-suppressed snoRNAs. SNORA7A restoration impairs H19-mediated osteogenesis and tumor suppression, indicating an oncogenic role of SNORA7A. TCGA analysis indicated that SNORA7A expression is associated with activation of oncogenic signaling and poor survival in cancer patients. Using an optimized streptavidin-binding RNA aptamer designed from H19 lncRNA, we revealed that H19-tethered protein complexes include proteins critical for DNA damage response and repair, confirming H19's tumor suppressor role. In summary, our findings demonstrate a critical role of H19-modulated SNORA7A expression in LFS-associated osteosarcomas.

Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming.

During development, hematopoietic stem and progenitor cells (HSPCs) arise from specialized endothelial cells by a process termed endothelial-to-hematopoietic transition (EHT). The genetic program driving human HSPC emergence remains largely unknown. We previously reported that the generation of hemogenic precursor cells from mouse fibroblasts recapitulates developmental hematopoiesis. Here, we demonstrate that human fibroblasts can be reprogrammed into hemogenic cells by the same transcription factors. Induced cells display dynamic EHT transcriptional programs, generate hematopoietic progeny, possess HSPC cell surface phenotype, and repopulate immunodeficient mice for 3 months. Mechanistically, GATA2 and GFI1B interact and co-occupy a cohort of targets. This cooperative binding is reflected by engagement of open enhancers and promoters, initiating silencing of fibroblast genes and activating the hemogenic program. However, GATA2 displays dominant and independent targeting activity during the early phases of reprogramming. These findings shed light on the processes controlling human HSC specification and support generation of reprogrammed HSCs for clinical applications.

The effect of Bruton's tyrosine kinase (BTK) inhibitors on collagen-induced platelet aggregation, BTK, and tyrosine kinase expressed in hepatocellular carcinoma (TEC).

OBJECTIVES: Bruton's tyrosine kinase (BTK) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) are expressed by human platelets. These kinases participate in platelet activation through the collagen receptor glycoprotein VI and may perform overlapping functions. In clinical studies, BTK inhibitors (ibrutinib, acalabrutinib, tirabrutinib, zanubrutinib) have been associated with increased bleeding risk, which may result from inhibition of BTK alone or of both BTK and TEC, although the role of TEC in bleeding risk remains unclear. METHODS: Here, in vitro catalytic and binding activities of ibrutinib and acalabrutinib were determined with four assay systems. Platelet aggregation assays determined inhibitor potency and its relationship to selectivity between BTK and TEC. RESULTS: Neither inhibitor was substantially more selective for BTK over TEC. The potencies at which BTK inhibitors suppressed platelet aggregation correlated with the potencies in on-target BTK assays, including those in cells. At clinically relevant plasma concentration, ibrutinib, acalabrutinib, and tirabrutinib inhibited collagen-induced platelet aggregation to a similar extent, despite differing in vitro IC50 s. CONCLUSIONS: Our results suggest BTK inhibition is the primary driver for inhibition of platelet aggregation. The subtle differences between these inhibitors suggest only randomized, double-blind, placebo-controlled clinical studies can fully address the bleeding risks of different BTK inhibitors.

Factors Correlated with Success Rate of Outpatient Smoking Cessation Services in Taiwan.

Smoking is the leading cause of preventable death. The purpose of this study was to explore the patient’s and physician’s factors that are correlated with smoking cessation success rate. A total of 877 smokers who visited the outpatient smoking cessation services at a medical center in Northern Taiwan were recruited for the study. Phone interviews were carried out six months after the initial visit to evaluate the success rate of smoking cessation. The result showed that the abstinence rate at six-month was 37.7%. By the multivariate logistic regression model, the predictive factors of abstinence were smokers who had a lower Fagerström test for cigarette dependence (FTCD), lower exhaled carbon monoxide (CO) concentration, or who smoked less than 20 cigarettes per day at the first visit. Smokers who had more than one smoking cessation outpatient visit or seen by physicians who, on average, delivered more than one smoking cessation consultations per week also led to a higher success rate. Therefore, we suggest that physicians should put more efforts and encourage follow-up visits for some smokers by knowing their characteristics at the first visit. Furthermore, physicians with more experience in smoking cessation consultation seemed to be more likely to help patients to quit smoking successfully.

Feeling bad about progress does not lead people want to change their health behaviour.

OBJECTIVE: When do people decide to do something about problematic health behaviours? Theoretical models and pragmatic considerations suggest that people should take action when they feel bad about their progress - in other words, when they experience negative progress-related affect. However, the impact of progress-related affect on goal striving has rarely been investigated. DESIGN AND METHODS: Study 1 (N = 744) adopted a cross-sectional design and examined the extent to which measures of progress-related affect were correlated with intentions to take action. Study 2 (N = 409) investigated the impact of manipulating progress-related affect on intentions and behaviour in an experimental design. RESULTS: Study 1 found that, while engaging in health behaviours had the expected affective consequences (e.g. people felt bad when they were not eating healthily, exercising regularly or limiting their alcohol consumption), it was feeling good rather than bad about progress that was associated with stronger intentions. Study 2 replicated these findings. Participants induced to feel good about their eating behaviour had marginally stronger intentions to eat healthily than participants led to feel bad about their eating behaviour. CONCLUSION: The findings have implications for interventions designed to promote changes in health behaviour, as well as theoretical frameworks for understanding self-regulation.

Deficiency in Neuronal TGF-ß Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-ß Signaling Protects against MPTP Neurotoxicity in Mice.

Transforming growth factor-ß (TGF-ß) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-ß signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-ß signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-ß signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF-ß signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.SIGNIFICANCE STATEMENT We show that reducing Transforming growth factor-ß (TGF-ß) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-ß signaling reduces neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a parkinsonism-inducing agent. Our results provide a rationale to pursue a means of increasing TGF-ß signaling as a potential therapy for Parkinson's disease.

Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton tyrosine kinase (BTK)-mediated B-cell receptor signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and follicular lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy. Mol Cancer Ther; 16(7); 1246-56. ©2017 AACR.