bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer
Authors: Cao Qi , Song Zhengshuai , Ruan Hailong , Wang Cheng , Yang Xiong , Bao Lin , Wang Keshan , Cheng Gong , Xu TianBo , Xiao Wen , Xiong Zhiyong , Liu Di , Yang Ming , Zhou Diwei , Yang Hongmei , Chen Ke , Zhang Xiaoping 
Published: December 2019

AbstractPurpose:Emerging evidence indicates that castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor (AR) or its V7 splice variant (AR-V7) and commonly becomes resistant to endocrine therapy. The aim of this work is to evaluate the function of a kinesin protein, KIF4A, in regulating AR/AR-V7 in prostate cancer endocrine therapy resistance.Experimental Design:We examined KIF4A expression in clinical prostate cancer specimens by IHC. Regulated pathways were investigated by qRT-PCR, immunoblot analysis, immunoprecipitation, and luciferase reporter and chromatin immunoprecipitation (ChIP) assays. A series of functional analyses were conducted in cell lines and xenograft models.Results:Examination of the KIF4A protein and mRNA levels in patients with prostate cancer showed that increased expression of KIF4A was positively correlated with androgen receptor (AR) levels. Patients with lower tumor KIF4A expression had improved overall survival and disease-free survival. Mechanistically, KIF4A and AR form an auto-regulatory positive feedback loop in prostate cancer: KIF4A binds AR and AR-V7 and prevents CHIP-mediated AR and AR-V7 degradation; AR binds the promoter region of KIF4A and activates its transcription. KIF4A promotes castration-sensitive and castration-resistant prostate cancer cell growth through AR- and AR-V7-dependent signaling. Furthermore, KIF4A expression is upregulated in enzalutamide-resistant prostate cancer cells, and KIF4A knockdown effectively reverses enzalutamide resistance and enhances the sensitivity of CRPC cells to endocrine therapy.Conclusions:These findings indicate that KIF4A plays an important role in the progression of CRPC and serves as a crucial determinant of the resistance of CRPC to endocrine therapy.
Exposure–Toxicity Association of Cyclophosphamide and Its Metabolites in Infants and Young Children with Primary Brain Tumors: Implications for Dosing
Authors: Campagne Olivia , Zhong Bo , Nair Sreenath , Lin Tong , Huang Jie , Onar-Thomas Arzu , Robinson Giles , Gajjar Amar , Stewart Clinton F. 
Published: December 2019

Abstract

Purpose:
To characterize the population pharmacokinetics of cyclophosphamide, active 4-hydroxy-cyclophosphamide (4OH-CTX), and inactive carboxyethylphosphoramide mustard (CEPM), and their associations with hematologic toxicities in infants and young children with brain tumors. To use this information to provide cyclophosphamide dosing recommendations in this population.

Patients and Methods:
Patients received four cycles of a 1-hour infusion of 1.5 g/m2 cyclophosphamide. Serial samples were collected to measure cyclophosphamide, 4OH-CTX, and CEPM plasma concentrations. Population pharmacokinetic modeling was performed to identify the patient characteristics influencing drug disposition. Associations between drug exposures and metrics reflecting drug-induced neutropenia, erythropenia, and thrombocytopenia were investigated. A Bayesian approach was developed to predict 4OH-CTX exposure using only cyclophosphamide and CEPM plasma concentrations.

Results:
Data from 171 patients (0.07–4.9 years) were adequately fitted by a two-compartment (cyclophosphamide) and one-compartment model (metabolites). Young infants (&lt;6 months) exhibited higher mean 4OH-CTX exposure than did young children (138.4 vs. 107.2 μmol/L·h, P &lt; 0.0001). No genotypes exhibited clinically significant influence on drug exposures. Worse toxicity metrics were significantly associated with higher 4OH-CTX exposures. Dosing simulations suggested decreased cyclophosphamide dosage to 1.2 g/m2 for young infants versus 1.5 g/m2 for children to attain similar 4OH-CTX exposure. Bayesian-modeled 4OH-CTX exposure predictions were precise (mean absolute prediction error 14.8% ± 4.2%) and had low bias (mean prediction error 4.9% ± 5.1%).

Conclusions:
A 4OH-CTX exposure–toxicity association was established, and a decreased cyclophosphamide dosage for young infants was suggested to reduce toxicity in this population. Bayesian modeling to predict 4OH-CTX exposure may reduce clinical processing–related costs and provide insights into further exposure–response associations.
Building on the Promise of Cancer Vaccines for Solid Tumors
Authors: Slingluff Craig L. 
Published: December 2019

Abstract
A novel telomerase vaccine (INVAC-1) has been evaluated in a phase I clinical trial (n = 26). It induced CD8+ and CD4+ T-cell responses and reduced circulating regulatory T cells. The findings support further development, especially in combination with vaccine adjuvants, plus therapies to increase immune infiltrates into solid tumor metastases.
See related article by Teixeira et al., p. 588
Combination Immunotherapy with Cytotoxic T-Lymphocyte–Associated Antigen-4 and Programmed Death Protein-1 Inhibitors Prevents Postoperative Breast Tumor Recurrence and Metastasis
Authors: Sun Ting , Zhang Wenjia , Li Yuan , Jin Zhengyu , Du Yang , Tian Jie , Xue Huadan 
Published: December 2019

Abstract

Postoperative tumor recurrence and metastasis remain an extreme challenge in breast cancer. Therapies that target cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have provided unprecedented clinical benefits in various types of cancer. The aim of this study was to determine whether the combination of anti-CTLA-4 and anti-PD-1 could prevent postoperative breast tumor recurrence and metastasis in breast tumor–bearing mice. The results indicated that the combination of CTLA-4 and PD-1 inhibitors was more effective compared with single inhibitors for mammary tumor growth and prevention of postsurgical tumor recurrence and pulmonary metastasis (P &lt; 0.05), which resulted in prolonged survival (P &lt; 0.05). Analysis of the underlying mechanism revealed that anti-CTLA-4 and anti-PD-1 in combination synergistically promoted the infiltration of CD8+ and CD4+ T cells into tumors (P &lt; 0.05 vs. single inhibitors), thus boosting the antitumor immune responses. In summary, our results revealed that combination immunotherapy with anti-CTLA-4 and anti-PD-1 may present a new, promising regimen to inhibit postoperative breast cancer relapse and lung metastasis and improve patient outcomes, which warrants further investigation in clinical settings.
Role of the Surface Boundary Conditions in Boreal Spring on the Interannual Variability of the Multistage Evolution of the East Asian Summer Monsoon
Authors: Oh Hyoeun , Ha Kyung-Ja 
Published: December 2019

AbstractThe seasonal movement of the upper-level jet plays a key role in the evolution of the East Asian summer monsoon (EASM). However, it remains unresolved how interannual changes in surface boundary conditions can influence the upper-level flow over East Asia, thereby modulating the onset of the EASM. Here we capture the timing of multistage evolution over East Asia using the upper-level zonal wind in a two-phase linear regression model. In addition, we show the impact of two surface boundary conditions on the timing of the EASM onset related to the strength of the upper-level zonal wind: 1) eastern Eurasian snow cover and 2) western North Pacific (WNP) sea surface temperature (SST) tendency. The eddy heat fluxes induced by the enhanced eastern Eurasian snow cover develop an anomalous anticyclonic circulation to the northwest, which causes anomalous warm southwesterly flow toward the north. These can make a reversal of the meridional temperature gradient, which results in the early monsoon onset via changes in the upper-level jet. The upper-level jet also responds to the SST tendency in April over the WNP via thermal wind balance and the resultant changes in transient eddy-induced heat transport. Our findings suggest potential sources for seasonal predictability in the interannual EASM onset dates.
Recovery of renal function in patients with lupus nephritis and reduced renal function: the beneficial effect of hydroxychloroquine
Authors: Lee J S , Oh J S , Kim Y-G , Lee C-K , Yoo B , Hong S 
Published: December 2019

Background Reduced renal function is associated with worse renal outcome in patients with lupus nephritis (LN). However, there is insufficient knowledge regarding renal function recovery in patients with LN with reduced baseline renal function. Therefore, the present study aimed to investigate renal function recovery and related factors in patients with reduced baseline renal function. Methods The present retrospective longitudinal cohort study included patients with LN and reduced renal function. Reduced renal function was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. Recovery of renal function was determined by an eGFR of >60 mL/min/1.73 m2 at six months after baseline, and factors associated with it were evaluated using logistic regression analysis. Results We included 90 patients with LN, with a mean eGFR value of 37.2 ± 13.9 mL/min/1.73 m2. Forty-six (51.1%) patients recovered their renal function after six months. On multivariate analysis, hydroxychloroquine use (odds ratio (OR) = 3.891, 95% confidence interval (CI) 1.196–12.653, p = 0.024), prolonged LN (OR = 0.926, 95% CI 0.874–0.981, p = 0.009) and high-grade tubular atrophy (OR = 0.451, 95% CI 0.208–0.829, p = 0.013) were associated with renal function recovery. During follow up, 25 patients were on end-stage renal disease (ESRD). Kaplan–Meier analysis revealed that renal function recovery after six months and lower probability of ESRD are associated. Conclusions In patients with LN and reduced renal function, renal function recovery at six months was associated with use of hydroxychloroquine and inversely related to longer duration of LN and higher grade of tubular atrophy.
Engagement barriers and service inequities in the NHS Breast Screening Programme: Views from British-Pakistani women
Authors: Woof Victoria G , Ruane Helen , Ulph Fiona , French David P , Qureshi Nadeem , Khan Nasaim , Evans D Gareth , Donnelly Louise S 
Published: December 2019

Objectives Previous research has largely attempted to explore breast screening experiences of South Asian women by combining opinions from Pakistani, Bangladeshi, and Indian women. This research often fails to reach the most underserved sub-groups of this population, with socioeconomic status not routinely reported, and English fluency being a participation requirement. With uptake low amongst British-Pakistani women, this study explores the experiences these women encounter when accessing the NHS Breast Screening Programme. Methods 19 one-to-one semi-structured interviews were carried out with British-Pakistani women from East Lancashire, UK. 14 interviews were conducted via an interpreter. Results Data were analysed using thematic analysis. Three themes were identified: ‘Absence of autonomy in screening and healthcare access’ describes how currently the screening service does not facilitate confidentiality or independence. Access requires third-party intervention, with language barriers preventing self-expression. ‘Appraisal of information sources’ makes distinctions between community and NHS communication. Whereas community communication was invaluable, NHS materials were deemed inaccessible due to translation incongruences and incomprehensible terminology. ‘Personal suppositions of breast screening’ explores the subjective issues associated with disengagement, including, the cultural misalignment of the service, and perceiving screening as a symptomatic service. Conclusions British-Pakistani women face some unique challenges when accessing breast screening. To promote uptake, the service needs to address the translation of screening materials and optimize upon community networks to disseminate knowledge, including knowledge of the screening environment within the context of culture to promote informed choice about attendance.
Regional changes in thalamic shape and volume are related to cognitive performance in multiple sclerosis
Authors: Bisecco Alvino , Capuano Rocco , Caiazzo Giuseppina , d’Ambrosio Alessandro , Docimo Renato , Cirillo Mario , Russo Antonio , Altieri Manuela , Bonavita Simona , Rocca Maria A , Filippi Massimo , Tedeschi Gioacchino , Gallo Antonio 
Published: December 2019

Background: The relationship between cognitive performance and regional thalamic atrophy in multiple sclerosis (MS) has been investigated in recent studies. Objective and methods: To further assess this relationship, 118 relapsing-remitting MS patients and 52 healthy controls underwent a neuropsychological assessment and a 3T-MRI (3-Tesla magnetic resonance imaging). Cognitive performances were correlated with thalamic shape changes by using Vertex Analysis. Results: Information processing speed performance correlated with atrophy of frontal/motor-connected thalamic sub-regions. Inhibitory control performance correlated with atrophy of all thalamic sub-regions. Global cognitive status correlated with atrophy of frontal/temporal-connected sub-regions. Conclusions: These findings support the hypothesis that, within the thalamus, the damage of the anterior regions is most relevant for cognitive dysfunction.
Safety of long-term intrathecal methotrexate in progressive forms of MS
Authors: Stark James W. , Josephs Lena , Dulak Deirdre , Clague Madison , Sadiq Saud A. 
Published: December 2019

Background: There are few treatment options for multiple sclerosis (MS) patients with advanced disability [expanded disability status scale (EDSS) ⩾ 6.0]. In 2010, we reported initial results of using intrathecal methotrexate (ITMTX) in patients with progressive MS. We now report on long-term use of ITMTX. We performed a retrospective chart analysis of patients who have had 18 or more treatments to establish the ongoing safety and tolerability of ITMTX. Thus, the objective of this study was to establish the safety and tolerability of long-term therapy with (ITMTX) in patients with treatment-resistant, progressive forms of MS. Methods: We studied 83 patients (67 secondary and 16 primary progressive) who received ITMTX 12.5 mg every 8–11 weeks for 3–10 years (range: 18–57 treatments). All patients were evaluated neurologically, and their EDSS was assessed at every treatment. In addition, all adverse events, frequency of infections, and any hospitalizations, were noted. Results: There were no deaths, hospitalizations, or other serious adverse effects related to ITMTX. Headaches occurred at least once in 12% of patients, and transient fatigue occurred in 53% of patients. As determined by EDSS, there was no significant change from baseline status to post-treatment scores in both primary progressive MS (PPMS) and secondary progressive (SPMS) patients. Conclusions: Pulsed ITMTX was well tolerated for up to 10 years in PPMS patients with no serious adverse effects. Although this was an open-label, retrospective analysis, and efficacy could not be studied, there was evidence of disease stabilization in many patients receiving ITMTX. It appears that long-term ITMTX is a safe therapeutic option in advanced progressive MS.
Variability in total shoulder arthroplasty planning software compared to a control CT-derived 3D printed scapula
Authors: Shah Sarav S , Sahota Shawn , Denard Patrick J , Provencher Matthew T , Parsons Bradford O , Hartzler Robert U , Dines Joshua S 
Published: December 2019

Background Two techniques exist from which all 3D preoperative planning software for total shoulder arthroplasty are based. One technique is based on measurements constructed on the mid-glenoid and scapular landmarks (Landmark). The second is an automated system using a best-fit sphere technique (Automated). The purpose was to compare glenoid measurements from the two techniques against a control computed tomography-derived 3D printed scapula. Methods Computed tomography scans of osteoarthritic shoulders of 20 patients undergoing primary total shoulder arthroplasty were analyzed with both 3D planning software techniques. Measurements from a 3D printed scapula (Scapula) from the true 3D computed tomography scan served as controls. Glenoid version and inclination measurements from each group were blinded and reviewed. Results In 65% (Automated) and 45% (Landmark) of cases, either inclination or version varied by 5° or more versus 3D printed scapula. Significant variability in version differences compared to the scapula group existed (p = 0.007). Glenoid version from the Scapula = 13.0° ± 10.6°, Automated = 15.0° ± 13.9°, and Landmark = 12.2° ± 7.8°. Inclination from Scapula = 5.4° ± 7.9°, Automated = 6.1° ± 12.6°, and Landmark = 6.2° ± 9.1°. Discussion A high percentage of cases showed discrepancies in glenoid inclination and version values from both techniques. Surgeons should be aware that regardless of software technique, there is variability compared to measurements from a control 3D computed tomography printed scapula.
A Clinicoradiological and Functional Evaluation of Lapidus Surgery for Moderate to Severe Bunion Deformity Shows Excellent Stable Correction and High Long-Term Patient Satisfaction
Authors: Jagadale Vivek S. , Thomas Ruth L. 
Published: December 2019

Background. Lapidus surgery involving arthrodesis of the first metatarsocuneiform (MTC) joint is an effective procedure for the correction of moderate to severe hallux valgus. The aim of this study was to collect and analyze radiographic data from our institution and determine the extent of first metatarsal shortening associated with the Lapidus procedure. Materials and Methods. A total of 53 patients (54 feet) who underwent arthrodesis of the first MTC joint combined with modified McBride bunionectomy for correction of moderate to severe hallux valgus deformity, between 2010 and 2015 were included in this study. Complete radiographic evaluation and AOFAS (American Orthopaedic Foot and Ankle Surgery) scoring was available for 54 feet. The average preoperative hallux valgus angulation (HVA) was 32° and the average intermetatarsal angle (IMA) was 16°. Results. Excluding 2 patients with postoperative hallux varus the average postoperative HVA correction at last follow-up was 14°. Average postoperative IMA was 9°. Although there was minimal bone resection during preparation of the MTC joint, no significant shortening of the first metatarsal was observed with this procedure. The relative length of the first metatarsal to the second metatarsal changed only 1.3%. Nonunion of the first MTC joint occurred in 10.3%, but only 1 foot was symptomatic requiring revision. The average postoperative hallux AOFAS score was 80.8. In sum, 63% of patients were very satisfied, 27% satisfied with reservations, and 10% were dissatisfied. Conclusion. The Lapidus bunion procedure offers excellent stable correction of moderate to severe hallux valgus deformity with minimal shortening of the first metatarsal and thereby higher patient satisfaction. Levels of Evidence: Level IV: Retrospective case series
Religious and Traditional Belief Systems Coexist and Compete with Science for Cultural Authority in West Africa
Authors: Falade Bankole 
Published: December 2019

This study examines the coexistence of science with Christian, Islamic and African religious beliefs and its implications for science communication. Using Moscovici's social representations theory and focusing on his accommodation hypothesis, the paper draws from experiences in mental health care, vaccination controversies and viral epidemics using case studies from West Africa. It also draws similarities from historical vaccination controversies around the world and the Zika virus epidemic in Brazil. The paper shows that Moscovici's accommodation hypothesis of cognitive polyphasia better explains the coexistence of science and religious belief, which can, however, be double-edged. It also shows that coexistence can lead to a positive cross-referral system, as in the case of mental health in Ghana; can have initial negative outcomes, as in vaccination campaigns in Nigeria and Cameroon; or can aid the spread and eventual containment of disease, as experienced during the Ebola virus disease epidemic in West Africa. Thus, while science remains a reference beacon in all controversies, its coexistence with religious belief can lead to an initial plunge in authority from which it eventually recovers. The choice of authority is also complicated by the dual role of some scientists as religious leaders and by previous untoward experiences with science, conspiracy theories and rumours about Western interventions in Africa.
Medical management of deeply infiltrating endometriosis - 7 year experience in a tertiary endometriosis centre in London
Authors: Wild Marianne , Miskry Tariq , Al-Kufaishi Asmaa , Rose Gillian , Crofton Mary 
Published: December 2019

Abstract
Background
Deeply infiltrating endometriosis has an estimated prevalence of 1% in women of reproductive age. Ninety percent have rectovaginal lesions but disease may also include the bowel, bladder and ureters. Current practice often favours minimally invasive surgical excision; however, there is increasing evidence that medical management can be as effective as long as obstructive uropathy and bowel stenosis are excluded. Our objective was to establish the proportion of women with deeply infiltrating endometriosis successfully managed with hormonal therapies within our tertiary endometriosis centre in West London. Secondary analysis was performed on anonymised data from the Trust’s endometriosis database.

Results
One hundred fifty-two women with deeply infiltrating endometriosis were discussed at our endometriosis multidisciplinary meeting between January 2010 and December 2016. Seventy-five percent of women underwent a trial of medical management. Of these, 44.7% did not require any surgical intervention during the study period, and 7.9% were symptomatically content but required interventions to optimise their fertility prospects. Another 7.0% were successfully medically managed for at least 12 months, but ultimately required surgery as their symptoms deteriorated. 26.5% took combined oral contraceptives, 14.7% oral progestogens, 1.5% progestogen implant, 13.2% levonorgestrel intrauterine device, 22.1% gonadotrophin-releasing hormone analogues, and 22.1% had analogues for 3–6 months then stepped down to another hormonal contraceptive. All women who underwent serial imaging demonstrated improvement or stable disease on MRI or ultrasound.

Conclusions
Medical treatments are generally safe, well tolerated and inexpensive. More than half (52.6%) of women were successfully managed with medical therapy to control their symptoms. This study supports the growing evidence supporting hormonal therapies in the management of deeply infiltrating endometriosis. The findings may be used to counsel women on the likely success rate of medical management.