bluuebunny/crossref_metadata_2025 huggingface dataset:
Repression of mitochondrial metabolism for cytosolic pyruvate-derived chemical production in Saccharomyces cerevisiae
Authors: Morita Keisuke , Matsuda Fumio , Okamoto Koji , Ishii Jun , Kondo Akihiko , Shimizu Hiroshi
Published: October 2019

Background

Saccharomyces cerevisiae is a suitable host for the industrial production of pyruvate-derived chemicals such as ethanol and 2,3-butanediol (23BD). For the improvement of the productivity of these chemicals, it is essential to suppress the unnecessary pyruvate consumption in S. cerevisiae to redirect the metabolic flux toward the target chemical production. In this study, mitochondrial pyruvate transporter gene (MPC1) or the essential gene for mitophagy (ATG32) was knocked-out to repress the mitochondrial metabolism and improve the production of pyruvate-derived chemical in S. cerevisiae.

Results

The growth rates of both aforementioned strains were 1.6-fold higher than that of the control strain. 13C-metabolic flux analysis revealed that both strains presented similar flux distributions and successfully decreased the tricarboxylic acid cycle fluxes by 50% compared to the control strain. Nevertheless, the intracellular metabolite pool sizes were completely different, suggesting distinct metabolic effects of gene knockouts in both strains. This difference was also observed in the test-tube culture for 23BD production. Knockout of ATG32 revealed a 23.6-fold increase in 23BD titer (557.0 ± 20.6 mg/L) compared to the control strain (23.5 ± 12.8 mg/L), whereas the knockout of MPC1 revealed only 14.3-fold increase (336.4 ± 113.5 mg/L). Further investigation using the anaerobic high-density fermentation test revealed that the MPC1 knockout was more effective for ethanol production than the 23BD production.

Conclusion

These results suggest that the engineering of the mitochondrial transporters and membrane dynamics were effective in controlling the mitochondrial metabolism to improve the productivities of chemicals in yeast cytosol.
Heterologous overexpression of bacterial hemoglobin VHb improves erythritol biosynthesis by yeast Yarrowia lipolytica
Authors: Mirończuk Aleksandra M. , Kosiorowska Katarzyna E. , Biegalska Anna , Rakicka-Pustułka Magdalena , Szczepańczyk Mateusz , Dobrowolski Adam
Published: October 2019

Background

Yarrowia lipolytica is an unconventional yeast with a huge industrial potential. Despite many advantages for biotechnological applications, it possesses enormous demand for oxygen, which is a bottleneck in large scale production. In this study a codon optimized bacterial hemoglobin from Vitreoscilla stercoraria (VHb) was overexpressed in Y. lipolytica for efficient growth and erythritol synthesis from glycerol in low-oxygen conditions. Erythritol is a natural sweetener produced by Y. lipolytica under high osmotic pressure and at low pH, and this process requires high oxygen demand.

Results

Under these conditions the VHb overexpressing strain showed mostly yeast-type cells resulting in 83% higher erythritol titer in shake-flask experiments. During a bioreactor study the engineered strain showed higher erythritol productivity (QERY = 0.38 g/l h) and yield (YERY = 0.37 g/g) in comparison to the control strain (QERY = 0.30 g/l h, YERY = 0.29 g/g). Moreover, low stirring during the fermentation process resulted in modest foam formation.

Conclusions

This study showed that overexpression of VHb in Y. lipolytica allows for dynamic growth and efficient production of a value-added product from a low-value substrate.
The historical roots and seminal research on health equity: a referenced publication year spectroscopy (RPYS) analysis
Authors: Yao Qiang , Li Xin , Luo Fei , Yang Lianping , Liu Chaojie , Sun Ju
Published: October 2019

Background

Health equity is a multidimensional concept that has been internationally considered as an essential element for health system development. However, our understanding about the root causes of health equity is limited. In this study, we investigated the historical roots and seminal works of research on health equity.

Methods

Health equity-related publications were identified and downloaded from the Web of Science database (n = 67,739, up to 31 October 2018). Their cited references (n = 2,521,782) were analyzed through Reference Publication Year Spectroscopy (RPYS), which detected the historical roots and important works on health equity and quantified their impact in terms of referencing frequency.

Results

A total of 17 pronounced peaks and 31 seminal works were identified. The first publication on health equity appeared in 1966. But the first cited reference can be traced back to 1801. Most seminal works were conducted by researchers from the US (19, 61.3%), the UK (7, 22.6%) and the Netherlands (3, 9.7%). Research on health equity experienced three important historical stages: origins (1800–1965), formative (1966–1991) and development and expansion (1991–2018). The ideology of health equity was endorsed by the international society through the World Health Organization (1946) declaration based on the foundational works of Chadwick (1842), Engels (1945), Durkheim (1897) and Du Bois (1899). The concept of health equity originated from the disciplines of public health, sociology and political economics and has been a major research area of social epidemiology since the early nineteenth century. Studies on health equity evolved from evidence gathering to the identification of cost-effective policies and governmental interventions.

Conclusion

The development of research on health equity is shaped by multiple disciplines, which has contributed to the emergence of a new stream of social epidemiology and political epidemiology. Past studies must be interpreted in light of their historical contexts. Further studies are needed to explore the causal pathways between the social determinants of health and health inequalities.
Platinum–gold nanoraspberries as effective photosensitizer in anticancer photothermal therapy
Authors: Depciuch J. , Stec M. , Klebowski B. , Baran J. , Parlinska-Wojtan M.
Published: October 2019

Background

New nanophotosensitizers for photothermal cancer therapy (PTT) are still sought. In this paper we propose fancy shaped, non agglomerated core/shell PtAu NRs nanoraspberries (PtAu NRs) as potential nanophotosensitizers in PTT.

Results

Light microscopy images of two colon cancer cell lines (SW480, SW620) showed, that the laser irradiation combined with PtAu NRs caused visible changes in the cell morphology. Fourier Transform InfraRed (FTIR) and Raman spectroscopies showed chemical changes in the DNA, phospholipids, lipids and protein structures caused by laser irradiation in the presence of PtAu NRs. The MTS assay showed ~ 25% mortality of cancer cells due to the addition of PtAu NRs to the cell culture, while for laser irradiation combined with nanoparticles, the mortality of cancer cells increased to 65% for the 650 nm laser and to 60% for the 808 nm laser. The calculated photothermal conversion efficiency reached 62% and 51% for the 650 nm and 808 nm lasers, respectively.

Conclusions

PtAu NRs could be applied as effective light-absorbers in the PTT anticancer therapy.
Neighborhood walkability and 12-year changes in cardio-metabolic risk: the mediating role of physical activity
Authors: Chandrabose Manoj , Cerin Ester , Mavoa Suzanne , Dunstan David , Carver Alison , Turrell Gavin , Owen Neville , Giles-Corti Billie , Sugiyama Takemi
Published: October 2019

Background

Living in walkable neighborhoods may provide long-term cardio-metabolic health benefits to residents. Little empirical research has examined the behavioral mechanisms in this relationship. In this longitudinal study, we examined the potential mediating role of physical activity (baseline and 12-year change) in the relationships of neighborhood walkability with 12-year changes in cardio-metabolic risk markers.

Methods

The Australian Diabetes, Obesity and Lifestyle study collected data from adults, initially aged 25+ years, in 1999–2000, 2004–05, and 2011–12. We used 12-year follow-up data from 2023 participants who did not change their address during the study period. Outcomes were 12-year changes in waist circumference, weight, systolic and diastolic blood pressure, fasting and 2-h postload plasma glucose, high-density lipoprotein cholesterol, and triglycerides. A walkability index was calculated, using dwelling density, intersection density, and destination density, within 1 km street-network buffers around participants’ homes. Spatial data for calculating these measures were sourced around the second follow-up period. Physical activity was assessed by self-reported time spent in moderate-to-vigorous physical activity (including walking). Multilevel models, adjusting for potential confounders, were used to examine the total and indirect relationships. The joint-significance test was used to assess mediation.

Results

There was evidence for relationships of higher walkability with smaller increases in weight (P = 0.020), systolic blood pressure (P < 0.001), and high-density lipoprotein cholesterol (P = 0.002); and, for relationships of higher walkability with higher baseline physical activity (P = 0.020), which, in turn, related to smaller increases in waist circumference (P = 0.006), weight (P = 0.020), and a greater increase in high-density lipoprotein cholesterol (P = 0.005). There was no evidence for a relationship of a higher walkability with a change in physical activity during the study period (P = 0.590).

Conclusions

Our mediation analysis has shown that the protective effects of walkable neighborhoods against obesity risk may be in part attributable to higher baseline physical activity levels. However, there was no evidence of mediation by increases in physical activity during the study period. Further research is needed to understand other behavioral pathways between walkability and cardio-metabolic health, and to investigate any effects of changes in walkability.
Ipsilateral breast metastasis after axillary dissection caused by epithelioid sarcoma: a case report and pathological investigation
Authors: Chen Luyan , Wang Li , Zhang Xiaochen , Yao Minya , Fu Peifen
Published: October 2019

Background

Epithelioid sarcoma (ES) is a rare malignant soft tissue tumor, commonly occurring in distal extremities, such as fingers, hands and wrists. For oncologists and surgeons, a female patient with enlarged axillary lymph node on one side only is easily diagnosed with an occult breast carcinoma rather than ES. Besides, whole breast metastasis of ES has not been reported yet.

Case presentation

A 47-year-old Chinese woman came to the outpatient clinic of First Affiliated Hospital of Zhejiang University (FAHZU) with a complaint of an asymptomatic right axillary mass for 3 months. Then she received surgical resection of the right axillary lymph nodes and right supraclavicular lymph nodes. According to the clinical tumor site and routine immunohistochemistry (IHC), suspicion of metastatic epithelial sarcoma and metastatic breast cancer could not be ruled out. Subsequently, with more detailed medical history review and physical examination, a mass on the right forearm was found, which was considered as the primary lesion. Further IHC and Molecular Genetics revealed that all the neoplastic cells exhibited loss of INI1 protein and were negative for ERG gene rearrangement yet positive for epithelial membrane antigen (EMA), cytokeratin (CK) 8, CK19, Vimentin, CD34. The final diagnosis was ES. She received postoperative chemotherapy, without radiotherapy. Unexpectedly, an ipsilateral breast metastasis was developed at ten months after surgery. Regrettably, there was no positive result of the metastatic breast sample, based on a genome sequencing by a 381-cancer-gene panel in a lab. Therefore, she went through another round of chemotherapy and took Apatinib for maintenance treatment. During the last follow-up (26 months after diagnosis), the disease was under control.

Conclusion

This rare but interesting case enables breast surgeons and pathologists to accumulate more experience of differential diagnosis of axillary mass for personalized treatment in clinical practice. Meanwhile, ipsilateral breast metastasis of ES we reported in the case urges that clinicians attach greater importance to the tumor metastasis mechanism.
Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants
Authors: Liu Keqiang , Xu Wenshuai , Tian Xinlun , Xiao Meng , Zhao Xinyue , Zhang Qianli , Qu Tao , Song Jiaxing , Liu Yaping , Xu Kai-Feng , Zhang Xue
Published: October 2019

Background

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant disease featured by lung cysts, spontaneous pneumothorax, fibrofolliculomas and renal tumors. The causative gene for BHDS is the folliculin (FLCN) gene and more than 200 mutations have been reported in FLCN, mostly truncating mutations. The aim of this study is to better characterize the clinical features and mutation spectrum of Chinese BHDS patients and to systematically evaluate the effects of non-truncating mutations on mRNA splicing pattern.

Methods

We enrolled 47 patients from 39 unrelated families with symptoms highly suggestive of BHDS after informed consent and detailed clinical data were collected. Exon sequencing followed by multiplex ligation-dependent probe amplification testing were applied for mutation screening. The effects of non-truncating mutations, including 15 missense mutations and 6 in-frame deletions, on mRNA splicing were investigated by minigene assays.

Results

A total of 24 FLCN germline variants were found in 39 patients from 31 distinct families. Out of these patients, 100% (36/36) presented with lung cysts and 58.3% (21/36) had experienced spontaneous pneumothorax. Seventeen mutation carriers had skin lesions (47.2%, 17/36) and 9 (30%, 9/30) had kidney lesions including 8 with renal cysts and 1 with renal hamartoma. Among all detected variants 14 (58.3%, 14/24) were novel, including 11 variants classified to be pathogenic and 3 variants of uncertain significance. None of 21 non-truncating mutations changed the mRNA splicing pattern of minigenes.

Conclusions

We found different clinical features of Chinese BHDS patients compared with Caucasians, with more lung cysts and pneumothorax but fewer skin lesions and malignant renal cancer. Chinese patients with BHDS also have a different mutation spectrum from other races. Non-truncating mutations in FLCN did not disrupt mRNA splicing pattern, in turn supporting the hypothesis that these mutations impair folliculin function by disrupting the stability of the FLCN gene product.
Correction to: FAK-ERK activation in cell/matrix adhesion induced by the loss of apolipoprotein E stimulates the malignant progression of ovarian cancer
Authors: Lai Huiling , Zhao Xuejiao , Qin Yu , Ding Yi , Chen Ruqi , Li Guannan , Labrie Marilyne , Ding Zhiyong , Zhou Jianfeng , Hu Junbo , Ma Ding , Fang Yong , Gao Qinglei
Published: October 2019

In the original publication of this manuscript [1], Fig. 5E lower panel was incorrect due to an error in the preparation of these figures for publication. It was noticed that in the lower panel of Fig. 5E, one mouse image of ApoE−/− + PBS group (upper) was a photograph coming from ApoE−/− + BAPN pre-treatment group (lower). The corrected figure appears below. We apologize for any confusion this may have caused.
Age at onset of training in children with hearing and speech disorders and the analysis of related factors in Turkey
Authors: Sahli Ayse Sanem
Published: October 2019

Background

Early diagnosis and intervention play a vital role in hearing and speech disorders and the effect of intervention varies according to the age at onset of training of children with such disorders. Aim of this study is to investigate the age at onset of training in children admitted to our center with complaints of hearing and speech disorder, and the related factors.

Methods

In the first phase of the study, data of 473 children admitted to our center between January 2015 and October 2018 with complaints of hearing and speech disorders and no additional disability were retrospectively analyzed. Then, their chronological age, gender, cause of admission, age at onset of training and the effect of factors that may have an impact on the age at onset of training were analyzed statistically. Study data were obtained from patient records.

Results

Of 473 children (350 males and 123 females) admitted to our training center with the complaints of hearing and speech disorders, 252 (53.3%) were presented with speech sound disorders, 90 (19.0%) with stuttering, 87 (18.4%) with delayed speech, 32 (6.8%) with hearing loss and 12 (2.5%) with other causes. Although there was a statistically significant difference between the age at onset of training and the factors; such as cause of admission, parental education level, employment status of the mother, occupation of the father, and socioeconomic status of the family(p < 0.05),no statistically significant difference was found between the age at onset of training and gender(p > 0.05).

Conclusions

The study revealed that children with hearing loss have the chance of early diagnosis thanks to neonatal hearing screening programs and that they commence their training until the age of 2, which is considered to be a critical period for language and speech development. However, it is an undeniable fact that we have not yet reached the ideal age for the commencement of training (6th month). Similarly, the age of diagnosis and initiation of training is delayed in children with speech disorders due to families’ delayed referral to the training centers.
The TREATT Trial (TRial to EvaluAte Tranexamic acid therapy in Thrombocytopenia): safety and efficacy of tranexamic acid in patients with haematological malignancies with severe thrombocytopenia: study protocol for a double-blind randomised controlled trial
Authors:   on behalf of the TREATT Trial Collaboration (provisional), Estcourt Lise J. , McQuilten Zoe , Powter Gillian , Dyer Claire , Curnow Eleanor , Wood Erica M. , Stanworth Simon J.
Published: October 2019

Background

Patients with haematological malignancies often develop thrombocytopenia as a consequence of either their disease or its treatment. Platelet transfusions are commonly given to raise a low platelet count and reduce the risk of clinical bleeding (prophylaxis) or stop active bleeding (therapy). Recent studies have shown that many patients continue to experience bleeding despite the use of prophylactic platelet transfusions. Tranexamic acid is an anti-fibrinolytic, which reduces the breakdown of clots formed in response to bleeding. Anti-fibrinolytics have been shown to prevent bleeding, decrease blood loss and use of red cell transfusions in elective and emergency surgery, and are used widely in these settings. The aim of this trial is to test whether giving tranexamic acid to patients receiving treatment for haematological malignancies reduces the risk of bleeding or death and the need for platelet transfusions.

Methods

This is a multinational randomised, double-blind, placebo-controlled, parallel, superiority trial. Patients will be randomly assigned to receive tranexamic acid (given intravenously or orally) or a matching placebo in a 1:1 ratio, stratified by site. Patients with haematological malignancies receiving intensive chemotherapy or stem cell transplantation (or both) who are at least 18 years of age and expected to become severely thrombocytopenic for at least 5 days will be eligible for this trial. The primary outcome of the trial is the proportion of patients who died or had bleeding of World Health Organization grade 2 or above during the first 30 days of the trial. We will measure the rates of bleeding daily by using a short, structured assessment of bleeding, and we will record the number of transfusions given to patients. We will assess the risk of arterial and venous thrombosis for 120 days from the start of trial treatment.

Discussion

This trial will assess the safety and efficacy of using prophylactic tranexamic acid during a period of intensive chemotherapy and associated thrombocytopenia in people with haematological disorders.

Trial registration

This study was prospectively registered on Current Controlled Trials on 25 March 2015 (ISRCTN73545489) and is also registered on ClinicalTrials.gov (NCT03136445).
Invariant natural killer T cells are functionally impaired in patients with systemic sclerosis
Authors: Pecher Ann-Christin , Kettemann Felix , Asteriti Elisa , Schmid Hannes , Duerr-Stoerzer Silke , Keppeler Hildegard , Henes Joerg Christoph , Klein Reinhild , Hinterleitner Clemens , Secker Kathy-Ann , Schneidawind Corina , Kanz Lothar , Schneidawind Dominik
Published: October 2019

Background

Systemic sclerosis (SSc) is a potentially fatal autoimmune disease that leads to extensive fibrosis of the skin and internal organs. Invariant natural killer T (iNKT) cells are potent immunoregulatory T lymphocytes being able to orchestrate dysregulated immune responses. The purpose of this study was to evaluate numbers and function of iNKT cells in patients with SSc and to analyze their correlation with disease parameters.

Methods

Human iNKT cells from 88 patients with SSc and 33 healthy controls were analyzed by flow cytometry. Their proliferative capacity and cytokine production were investigated following activation with CD1d ligand α-galactosylceramide (α-GalCer).

Results

We observed an absolute and relative decrease of iNKT cells in patients with SSc compared with healthy controls. Interestingly, the subtype of SSc, disease severity, or treatment with immunosuppressive drugs did not affect iNKT cell numbers. However, T helper (Th) cell immune polarization was biased towards a Th17 immunophenotype in SSc patients. Moreover, iNKT cells from patients with SSc showed a significantly decreased expansion capacity upon stimulation with α-GalCer.

Conclusion

iNKT cells are deficient and functionally impaired in patients with SSc. Therefore, adoptive transfer strategies using culture-expanded iNKT cells could be a novel approach to treat SSc patients.
Evaluation of the immunogenicity and efficacy of BCG and MTBVAC vaccines using a natural transmission model of tuberculosis
Authors: Roy Alvaro , Tomé Irene , Romero Beatriz , Lorente-Leal Víctor , Infantes-Lorenzo José A. , Domínguez Mercedes , Martín Carlos , Aguiló Nacho , Puentes Eugenia , Rodríguez Esteban , de Juan Lucía , Risalde María A. , Gortázar Christian , Domínguez Lucas , Bezos Javier
Published: October 2019

Effective vaccines against tuberculosis (TB) are needed in order to prevent TB transmission in human and animal populations. Evaluation of TB vaccines may be facilitated by using reliable animal models that mimic host pathophysiology and natural transmission of the disease as closely as possible. In this study, we evaluated the immunogenicity and efficacy of two attenuated vaccines, BCG and MTBVAC, after each was given to 17 goats (2 months old) and then exposed for 9 months to goats infected with M. caprae. In general, MTBVAC-vaccinated goats showed higher interferon-gamma release than BCG vaccinated goats in response to bovine protein purified derivative and ESAT-6/CFP-10 antigens and the response was significantly higher than that observed in the control group until challenge. All animals showed lesions consistent with TB at the end of the study. Goats that received either vaccine showed significantly lower scores for pulmonary lymph nodes and total lesions than unvaccinated controls. Both MTBVAC and BCG vaccines proved to be immunogenic and effective in reducing severity of TB pathology caused by M. caprae. Our model system of natural TB transmission may be useful for evaluating and optimizing vaccines.
A cross sectional survey of internet use among a highly socially disadvantaged population of tobacco smokers
Authors: McCrabb Sam , Twyman Laura , Palazzi Kerrin , Guillaumier Ashleigh , Paul Christine , Bonevski Billie
Published: October 2019

Background

Tobacco smoking is highest among population groups which are the most socially disadvantaged. Internet-based smoking cessation programs have been found to be effective, though rates of internet access are not well known in these groups. This study describes the rates of internet use and types of technology used to access the internet by a population of socially disadvantaged smokers. The study also examined relationships between sociodemographic and smoking behaviours with amount of internet use and type of device used.

Methods

A cross-sectional survey of 369 clients (response rate 77%) from two non-government community service organisations in metropolitan New South Wales, Australia was conducted using touchscreen computers. Descriptive statistics and logistic regressions were used to examine results.

Results

Eligible participants ranged from 19 to 88 years old current tobacco users. Over half (58%) of the participants reported weekly or more frequent use of the internet with less than a third (28%) not having any access. The odds of using the internet at least weekly decreased with age and as heaviness of smoking increased (OR = 0.94, p < 0.001; OR = 0.81, p = 0.022, respectively). Odds of internet use were higher as income increased (OR = 2.74, p < 0.001 for individuals earning $201–$400 per week; OR = 2.83, p = 0.006 for individuals earning > $400 per week). Device use differed for age and income.

Conclusions

Internet-based interventions appear to reach the majority of socially disadvantaged populations. It is expected that this reach will continue to grow, making internet-based interventions a potential platform for providing care to low socioeconomic individuals who smoke, however inequalities may be exacerbated for those individual without internet access.

Implications

Internet use among socially disadvantaged tobacco users is moderate (58%). An internet-based smoking cessation intervention for socially disadvantaged tobacco users may be an effective intervention however, older, heavier tobacco users may not benefit as easily due to limited internet access and therefore acknowledging these limitations when developing an intervention can help to acknowledge limitation of intervention reach.
Prospective pilot study of Floseal® for the treatment of anterior epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT)
Authors: Lee John M. , Wu Vincent , Faughnan Marie E. , Lasso Andrea , Figol Andrea , Kilty Shaun J.
Published: October 2019

Background

Epistaxis is the most common symptom of hereditary hemorrhagic telangiectasia (HHT), affecting more than 98% of adults with HHT, with significant impact on quality of life. Floseal® has been shown to be effective for the management of anterior epistaxis, but has yet to be thoroughly evaluated in this population. Our goal was to evaluate the efficacy of Floseal® for managing acute anterior epistaxis in patients with HHT.

Methods

A pilot prospective clinical trial was conducted at two tertiary referral centres, St. Michael's Hospital, Toronto, Canada and The Ottawa Hospital, Ottawa, Canada. All patients with HHT presenting with acute anterior epistaxis to the two study centres, who enrolled in the study, received Floseal® treatment. The primary outcome measures were achievement of hemostasis and changes in the Epistaxis Severity Score (ESS) between baseline and one-month follow up. Secondary outcome measure included clinical assessment of the nasal cavity.

Results

Seven patients were included in the final analysis. All patients underwent treatment of anterior epistaxis with Floseal® and achieved control of epistaxis within 15-min post-application. Application of Floseal® was well tolerated, with patients reporting a pain score of 3 ± 3.13 out of 10. There was no statistically significant difference noted in ESS scores pre-treatment and one-month follow up, 6.27 ± 2.42 vs. 4.50 ± 2.44, p = 0.179. There was a significant improvement clinically on exam of the nasal cavity between baseline and at one-month follow up, indicated by a decrease in the clinical assessment score, 17.29 ± 7.70 vs. 9.57 ± 7.81 ( p = 0.0088).

Conclusions

Patients with HHT presenting with acute epistaxis were able to achieve hemostasis with one application of Floseal®, with the procedure being very well tolerated with minimal pain. Although there was no significant change in ESS scores, clinical assessment of the nasal cavity revealed significant improvement at one-month follow up post treatment with Floseal®.

Trial registration

This multi-centered prospective clinical trial was registered with ClinicalTrials.gov ( NCT02638012 ). Registered on December 22, 2015.
Activity of crustal faults and the Xolapa sliver motion in Guerrero–Oaxaca forearc of Mexico, from seismic data
Authors: Kazachkina Ekaterina , Kostoglodov Vladimir , Husker Allen , Cotte Nathalie
Published: October 2019

Oblique convergent margins often host forearc slivers separated by the subduction interface and a trench parallel strike-slip fault system in the overriding plate. Mexican oblique subduction setting led to the formation of a forearc sliver and accomodation of part of the slip at the bounding system of strike-slip faults. The Xolapa sliver is, on average, a$$\sim 105$$∼105-km-wide crustal block located along the coast of Guerrero and Oaxaca states of Mexico, and is limited by a$$\sim 650$$∼650-km-long La Venta-Chacalapa fault zone. Two types of datasets, local catalog and Global CMT compilation, are used to estimate the motion of the Xolapa sliver using the rigid block model that describes the phenomenon of slip partitioning. According to the results obtained from local and Global CMT catalogs for selected subduction thrust earthquakes, the forearc sliver moves southeastwards with respect to the fixed North America plate at the rate of 10 ± 1 mm/year and 5.6 ± 0.8 mm/year, respectively. These velocities in general agree with the values obtained from long-term GPS observations (5–6 mm/year). The origin of the inconsistency between local and teleseismic estimates is attributed to a difference in the double couple focal mechanism parameters for two types of datasets. Convergence obliquity changes from$$10.42{^\circ }$$10.42∘and the rate of 58 mm/year to$$13.29{^\circ }$$13.29∘at the rate of 68 mm/year along the Guerrero and Oaxaca coast increasing from northwest to southeast; therefore, the Xolapa sliver is supposed to be stretched. However, the slip vector azimuths of thrust subduction earthquakes tend to approach plate convergence vectors southeastwards along the coast; so, we assume that this may produce the forearc block compression.
Mobile-deployed care management based on standardized ePRO and computer-interpretable guideline engine for Chinese lymphoma patients.
Authors: Ping Ling Yan , Song Yuqin , Zhang Tingting , Ying Zhi Tao , Zhang Chen , Xie Yan , Liu Weiping , Lin Ningjing , Tu Meifeng , Deng Lijuan , Hong Lingling , Zhu Jun
Published: October 2019

1

Background: To effectively assist lymphoma patients and their care-givers after their hospital discharge, a standard follow-up guideline for lymphoma patients was designed and encoded through a computer-interpret-able-guideline (CiG) engine and deployed through mobile-Web and mobile-Apps to ensure continuous care throughout the treatment and recovery processes. Methods: Scheduled tasks including ePRO questionnaires and requests for test results were sent for completion, and a virtual care management team was assigned to ensure compliance and respond to automatic triggered alerts. Attending oncologists also were given mobile-Apps to access the patients’ securely uploaded records and consult remotely to manage side-effects after discharge. The out-of-hospital record management and care coordination enabled the adjustment of treatment plans and the optimized unitilization of clinical resources. Results: During 2018, 1012 patients or their caregivers interacted with our team through the mobile platform after discharge. 856 individual patients uploaded enough information to be initiated in the mobile follow-up program. Approximately 30% of these patients were Beijing residents while the rest came from all over China. About half of these patients had follow-up tests done in other 387 hospitals or 52 clinics. Based on ePRO questionnaires submitted, 218 patients had 616 side-effect-symptom alerts triggered and followed up, in addition to patient-initiated mobile consultation with their attending oncologists. Lab results especially white blood cell counts, platelet counts, and neutrophil counts, contributed to the majority of test alerts managed by our team. Analysis of 8000+ anonymized questions identified clinical processes in need of optimization. A new patient education manual addressing frequently asked questions, and new processes such as chemo-regime scheduling were put in place. Conclusions: We have demonstrated the feasibility of a mobile-deployed care management process after discharge for lymphoma patients and their caregivers. We have initiated retrospective studies of impacts on our patients’ treatment compliance and quality of life.
Prognostic role of immunosenscence associated with index in elderly non-small cell lung cancer patients treated with an anti-PD-1 antibody.
Authors: Tanaka Tomohiro , Yoshida Tatsuya , Masuda Ken , Takeyasu Yuki , Shinno Yuki , Matsumoto Yuji , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Yamamoto Noboru , Ohe Yuichiro
Published: October 2019

100

Background: Immunosenescence, an age-related impairment of the immune system, dampens acquired immunity and promotes inflammation. Therefore, it could also influence the degree of effectiveness of immune checkpoint inhibitors. Methods: We retrospectively reviewed the data of 52 NSCLC patients aged ≧75 years old treated with nivolumab or pembrolizumab from December 2015 to April 2019. Immunosenescence was assessed by the modified Glasgow Prognostic Scale (mGPS), Neutrophil-to-lymphocyte ratio (NLR), and Charlson Comorbidity Index (CCI), which are related to nutrition, inflammation and comorbidity, respectively. The Cox proportional hazard model and Kaplan-Meier curves were used to identify factors associated with survival. Results: The median follow-up duration was 19.5M (IQR:1-41). The patient characteristics were as follows: median age 79.7 years; male/female ratio, 41/11; PS0/1/2/3, 10/32/8/2; adeno/squamous histology/others, 33/15/4;stage III/IV/recurrence, 2/26/24; PD-L1 (22C3) (%)unknown/0/1-49/50-100, 18/2/8/24; driver mutation status positive/negative, 11/41; nivolumab/pembrolizumab, 29/23; treatment line 1/2/3/4 or more, 28/15/3/6; median number of treatment cycles 7.0 (1-53). The overall response rate (ORR) and disease control rate (DCR) were29.1% and 56.2%, respectively. The median progression-free survival (PFS) was 4.2 months (95% CI 1.8-7.5). The mGPS was significantly associated with the DCR (High/Low = 37.5/68.8%, p = 0.02) and the PFS (score 0-1/2 = 4.1/0.6 months) (HR: 0.37, 95% CI 0.18-0.74, p <0.01). However, neither the CCI nor the NLR wasassociated with the PFS (CCI: High/Low = 3.8/1.8 months, p = 0.64, and NLR: High (>3.5)/Low (≦3.5) = 3.8/5.6 months, p = 0.89). Multivariate regression analysis identified the mGPS as a significant predictor of the PFS(HR: 0.40, p = 0.008). Conclusions: A high mGPS score was significantly associated with a lower DCR and shorter PFS in elderly NSCLC patients treated with anti-PD-1 antibody.
Tumor size and location affecting the treatment selection for solitary small recurrent hepatocellular carcinoma (≤3.0cm) after initial hepatectomy.
Authors: Chen Shuling , Peng Zhenwei , Xiao Han , Wei Mengchao , Kuang Ming
Published: October 2019

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Background: We aimed to investigate the optimal treatment modality between radiofrequency ablation (RFA) and repeated hepatectomy in the treatment of solitary recurrent HCC (rHCC) after hepatectomy, considering the influence of tumor size and location. Methods: From Jan 2009 to Dec 2016, 630 consecutive patients with solitary small rHCC (≤3.0cm) after initial hepatectomy who underwent RFA or repeated hepatectomy were enrolled in three tertiary referral centers. Patients were divided into four groups according to tumor size (≤ 2.0cm or > 2.0cm) and location (central or peripheral) respectively. Overall survival (OS) and recurrence-free survival (RFS) rates were compared between RFA and repeated hepatectomy in these four groups. Results: For central rHCC ≤ 2.0cm, the OS and RFS rates at 5 years after RFA were significantly higher than those after repeated hepatectomy (69.9% vs 53.1%, P= 0.001; 56.2% vs 42.6%, P= 0.038). For central rHCC > 2.0cm, the 5-year OS and RFS rates were not significantly different between repeated hepatectomy and RFA (55.9% vs 48.2%, P= 0.080; 27.0% vs 19.2%, P= 0.103). For peripheral tumors ≤ 2.0cm (58.8% vs. 47.7%, P= 0.001; 45.2% vs. 25.6%, P= 0.001) or > 2.0cm (62.6% vs. 45.4%, P= 0.001; 44.7% vs. 21.1%, P= 0.010), the OS and RFS rates at 5 years after repeated hepatectomy were both significantly higher than those after RFA. Complications were more common in patients after repeated hepatectomy than RFA, especially for central tumors. Conclusions: RFA might be the optimal treatment for patients with central rHCC ≤ 2.0 cm whereas repeated hepatectomy should be recommended for patients with peripheral tumors.
Correlation of radiotherapy with the prognosis of elderly patients with hormone receptor-positive breast cancer according to immunohistochemical subtyping.
Authors: Zhang Jin
Published: October 2019

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Background: The present study examined the effect of radiotherapy on recurrence and survival in elderly patients with hormone-receptor-positive early breast cancer. Methods: A retrospective analysis of 327 patients aged ≥65 years with stage I-II, hormone receptor positive breast cancer who underwent breast conserving surgery and received endocrine therapy (ET) or radiotherapy plus endocrine therapy (ET+RT) was performed. Both groups were divided into luminal A type and luminal B type subgroups. Evaluation criteria were 5-year disease free survival (DFS), local relapse rate (LRR), overall survival (OS), and distant metastasis rate (DMR). Results: There were significant differences in 5-year DFS (HR 1.59, 95% CI 1.15–2.19, P=0.005) and LRR (HR 3.33, 95% CI 1.51–7.34, P=0.003), whereas there were no significant differences in OS and DMR between the two groups. In luminal A type, there was no significant difference in 5-year DFS, LRR, OS, and DMR between the ET group and the ET+RT group. In luminal B type, there were statistically significant differences in 5-year DFS (HR 2.188, 95% CI 1.37–3.49, P=0.001), LRR (HR 5.447, 95% CI 1.65–17.98, P=0.005), and OS (HR 1.752, 95% CI 1.01–3.054, P=0.048) between the two groups. In the ET group, there were significant differences between luminal A type and luminal B type in 5-year DFS (HR 1.841, 95% CI 1.23–2.75, P=0.003) and OS (HR 1.763, 95% CI 1.07–2.91, P=0.026). Conclusions: After breast conserving surgery, radiotherapy can reduce the LRR and improve the DFS and OS of luminal B type elderly patients, whereas luminal A type elderly patients do not benefit from radiotherapy. Without radiotherapy, luminal A type patients have better DFS and OS than luminal B type patients.
Tumor infiltrating lymphocytes show in vitro cytotoxic activity against tumor cells in multiple cancers.
Authors: Akolkar Dadasaheb B , TS Karthiklal , Patil Revati , S Karthickbalan , Raj Sambath , Datar Rajan , Ghatale Renuka
Published: October 2019

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Background: There has been considerable research interest in recruiting immune cells of cancer patients to detect and destroy malignant cells. Various approaches have been attempted including activation of dendritic cells, chimeric antigen receptor T-cells, use of check point inhibitors and expansion and infusion of Tumor Infiltration Lymphocytes (TILs). TILs have however been successfully evaluated in only a few cancers such as Melanoma and Cervix. In order to explore the feasibility of using TILs for treatment of various solid organ cancers we hypothesized that their in vitro evaluation would establish preliminary viability of the approach. Methods: We isolated TILs from 3 patients with Ca Buccal Mucosa, 2 patients with Ca Cervix, 2 patients with Ca Breast and 1 patient each with Ca Bladder and Basal Cell Carcinoma. The explant cultures of primary/metastatic tumor tissues sections of minimum 3 mm3 size using appropriate growth medium in presence of T cell growth factor, interleukin 2 (IL2) was utilized for the propagation of TILs. TILs were expanded in meaningful numbers within three to four weeks of culture and characterized for in vitro cytotoxicity by live cell imaging and Interferon gamma release ((IGR) test. TCR gene repertoire sequencing was performed using Next Generation Sequencing (NGS) to accurately measure T cell diversity and clonal expansion. Results: TILs were isolated from 10 out of 10 patients with median number of TILs of 10 million / tissue section. The flow cytometric analysis revealed and confirmed the presence of various T cell markers in the TIL cultures generated. In vitro cytotoxicity analysis performed by live cell imaging and IGRs revealed high potency for tumor cell kill rate for the expanded TILs. TCR gene sequencing revealed clonal expansion in the TIL explant population. Conclusions: This study shows feasibility of TIL expansion from cohort of patients with multiple cancer types which can be utilized for large scale expansion and infusion in future clinical trials.
Clinical efficacy of combination therapies with androgen receptor antagonists for treatment of multiple refractory cancers.
Authors: Akolkar Dadasaheb B , Patil Darshana , Datta Vineet , Srinivasan Ajay , Datar Rajan
Published: October 2019

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Background: Androgen Receptor (AR) antagonists have been the mainstay of prostate cancer treatments. However, there is increasing interest in the use of anti-AR agents in treatment of other cancers such as Triple Negative Breast Cancer and Lung Cancer. AR antagonists are usually administered as single agents and rarely in combination with other cytotoxic or targeted agents. We hypothesized that administration of AR antagonists indicated by Encyclopedic Tumor Analysis (ETA) in synergistic combination with cytotoxic, targeted or other endocrine agents may afford clinical benefit for refractory cancers. Methods: We evaluated treatment response in a basket of 18 patients with various advanced refractory solid organ malignancies, who received personalized treatments based on ETA investigations. As part of ETA, freshly biopsied tumor tissue and blood samples were evaluated for various markers such as gene mutations (DNA), gene expression (RNA) and receptor proteins (immunohistochemistry). Finally, viable tumor cells from the freshly biopsied tissue were used in in vitro chemosensitivity analysis with a panel of cytotoxic and targeted therapy agents. Radiological disease status was evaluated retrospectively and treatment response as well as Progression Free Survival (PFS) was determined. Results: Among the 18 patients, there were 8 males (44%) and 10 females (56%) with median age of 58 years (range 28 – 79). Patients had received a median of 3 prior lines of treatment (range 1 – 14). All 18 patients received ETA guided combination treatments which included an AR blockade. 9 patients showed Partial Response ( PR) with an Objective Response Rate (ORR) of 50%. 5 patients (28%) showed stable disease for ≥3 months (Clinical Benefit Rate = 77.8%), while 4 patients (22%) showed disease progression. In 2 patients (11%) disease progressed at ~60 days and in the remaining 2 patients (11%) progression was seen at > 120 days. Treatments were well tolerated without severe adverse events. Conclusions: Androgen addicted, refractory solid organ tumors respond to combinations of cytotoxic, targeted and endocrine agents along with AR antagonists guided by ETA.
Anlotinib, vincristine, and irinotecan for advanced Ewing sarcoma after failure of standard multimodal therapy: A multicenter, two-cohort, phase Ib/II trial (NCT03416517).
Authors: Xu Jie , Xie Lu , Guo Wei , Sun Xin , Liu Kuisheng , Zheng Bingxin , Ren Ting , Huang Yi , Tang Xiaodong , Yan Taiqiang , Yang Rongli
Published: October 2019

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Background: Both protracted irinotecan and anti-angiogenesis therapy have shown promising results in Ewing sarcoma. We did this phase Ib/II trial to first define the proper dose of irinotecan in combination with anlotinib in Ewing sarcoma (phase Ib) and then evaluate efficacy (phase II). Methods: Patients diagnosed with recurrent or refractory Ewing sarcoma were enrolled and sub-classified into cohort A (≥16y) or cohort B ( < 16y). In the dose-defining phase Ib portion, anlotinib was given at a fixed dose of 12mg D1-14 every 21 days, while the de-escalated 3+3 design was used to detect the recommended dose of irinotecan in each cohort from an initial level of 20mg/m2/d dx5x2. Recommended phase 2 dose (RP2D) was defined as the highest dose at which no more than 30% patients experience a DLT in the first two courses. In the next dose-expanding phase II portion, the primary endpoint was objective response rate at 12 weeks (ORR12w). Results: 41 patients were finally enrolled with 29 in cohortA and 12 in cohortB. For cohortA, first 5 patients were treated at initial level in phase Ib portion, two of whom subsequently experienced delayed diarrhea as dose-limiting toxicity (DLT). Additional six patients were then treated at a lower dose of 15mg/m2. Since no more DLT was recorded, it was used as RP2D. 23/24 patients in cohort A phase II were available for response evaluation at 12 weeks, with one complete response (CR), 14 partial response (PR) , 2 stable disease (SD) and 6 progressive disease (PD). ORR12wwas 62.5%. For cohort B, no DLT was noticed in the first six patients treated at the initial level which was used as RP2D later. Finally, 12 patients were included in cohort B. ORR12wwas 83.3% with two CR, 8 PR and two PD. Although effective, cohort B were closed because of slow enrollment. Most common grade 3/4 adverse events were leukopenia (28.5%), neutropenia (24.4%), anemia (8.7%) and diarrhea (3.7%). The genotype of UGT1A1*1 and UGT1A1*28 were not associated with the risk of diarrhea. Conclusions: The combination of irinotecan and anlotinib demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in advanced Ewing sarcoma. Clinical trial information: NCT03416517.