bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of hip fracture in meat-eaters, pescatarians, and vegetarians: results from the UK Women’s Cohort Study
Authors: Webster James , Greenwood Darren C. , Cade Janet E. 
Published: August 2022

Abstract
Background
The risk of hip fracture in women on plant-based diets is unclear. We aimed to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in the UK Women’s Cohort Study and to determine if potential associations between each diet group and hip fracture risk are modified by body mass index (BMI).

Methods
UK women, ages 35–69 years, were classified as regular meat-eaters (≥ 5 servings/week), occasional meat-eaters (< 5 servings/week), pescatarian (ate fish but not meat), or vegetarian (ate neither meat nor fish) based on a validated 217-item food frequency questionnaire completed in 1995–1998. Incident hip fractures were identified via linkage to Hospital Episode Statistics up to March 2019. Cox regression models were used to estimate the associations between each diet group and hip fracture risk over a median follow-up time of 22.3 years.

Results
Amongst 26,318 women, 822 hip fracture cases were observed (556,331 person-years). After adjustment for confounders, vegetarians (HR (95% CI) 1.33 (1.03, 1.71)) but not occasional meat-eaters (1.00 (0.85, 1.18)) or pescatarians (0.97 (0.75, 1.26)) had a greater risk of hip fracture than regular meat-eaters. There was no clear evidence of effect modification by BMI in any diet group (p-interaction = 0.3).

Conclusions
Vegetarian women were at a higher risk of hip fracture compared to regular meat-eaters. Further research is needed to confirm this in men and non-European populations and to identify factors responsible for the observed risk difference. Further research exploring the role of BMI and nutrients abundant in animal-sourced foods is recommended.

Trial registration
ClinicalTrials.gov, NCT05081466
Synergistic effects on itaconic acid production in engineered Aspergillus niger expressing the two distinct biosynthesis clusters from Aspergillus terreus and Ustilago maydis
Authors: Wang Yaqi , Guo Yufei , Cao Wei , Liu Hao 
Published: August 2022

Abstract
Background
Itaconic acid (IA) is a versatile platform chemical widely used for the synthesis of various polymers and current methods for IA production based on Aspergillus terreus fermentation are limited in terms of process efficiency and productivity. To construct more efficient IA production strains, A. niger was used as a chassis for engineering IA production by assembling the key components of IA biosynthesis pathways from both A. terreus and Ustilago maydis.

Results
Recombinant A. niger S1596 overexpressing the A. terreus IA biosynthesis genes cadA, mttA, mfsA produced IA of 4.32 g/L, while A. niger S2120 overexpressing the U. maydis IA gene cluster adi1, tad1, mtt1, itp1 achieved IA of 3.02 g/L. Integration of the two IA production pathways led to the construction of A. niger S2083 with IA titers of 5.58 g/L. Increasing cadA copy number in strain S2083 created strain S2209 with titers of 7.99 g/L and deleting ictA to block IA degradation in S2209 created strain S2288 with IA titers of 8.70 g/L. Overexpressing acoA to enhance the supply of IA precursor in strain S2288 generated strain S2444 with IA titers of 9.08 g/L in shake flask.

Conclusion
Recombinant A. niger overexpressing the U. maydis IA biosynthesis pathway was capable of IA accumulation. Combined expression of the two IA biosynthesis pathways from A. terreus and U. maydis in A. niger resulted in much higher IA titers. Furthermore, increasing cadA copy number, deleting ictA to block IA degradation and overexpressing acoA to enhance IA precursor supply all showed beneficial effects on IA accumulation.
A novel quantitative prognostic model for initially diagnosed non-small cell lung cancer with brain metastases
Authors: Li Xiaohui , Gu Wenshen , Liu Yijun , Wen Xiaoyan , Tian Liru , Yan Shumei , Chen Shulin 
Published: August 2022

AbstractBackgroundThe prognosis of non-small cell lung cancer (NSCLC) with brain metastases (BMs) had been researched in some researches, but the combination of clinical characteristics and serum inflammatory indexes as a noninvasive and more accurate model has not been described.MethodsWe retrospectively screened patients with BMs at the initial diagnosis of NSCLC at Sun Yat-Sen University Cancer Center. LASSO-Cox regression analysis was used to establish a novel prognostic model for predicting OS based on blood biomarkers. The predictive accuracy and discriminative ability of the prognostic model was compared to Adjusted prognostic Analysis (APA), Recursive Partition Analysis (RPA), and Graded Prognostic Assessment (GPA) using concordance index (C-index), time-dependent receiver operating characteristic (td-ROC) curve, Decision Curve Analysis(DCA), net reclassification improvement index (NRI), and integrated discrimination improvement index (IDI).Results10-parameter signature's predictive model for the NSCLC patients with BMs was established according to the results of LASSO-Cox regression analysis. The C-index of the prognostic model to predict OS was 0.672 (95% CI = 0.609 ~ 0.736) which was significantly higher than APA,RPA and GPA. The td-ROC curve and DCA of the predictive model also demonstrated good predictive accuracy of OS compared to APA, RPA and GPA. Moreover, NRI and IDI analysis indicated that the prognostic model had improved prediction ability compared with APA, RPA and GPA.ConclusionThe novel prognostic model demonstrated favorable performance than APA, RPA, and GPA for predicting OS in NSCLC patients with BMs.
Sequential acid/reduction response of triblock copolymeric nanomicelles to release camptothecin and toll-like receptor 7/8 agonist for orchestrated chemoimmunotherapy
Authors: Ge Xiaoyan , Hao Yanyun , Li Hui , Zhao Huajun , Liu Yang , Liu Yutong , Li Xia , Chen Hongfei , Zou Jing , Zhang Shiying , Huang Lingling , Shan Gang , Zhang Zhiyue 
Published: August 2022

Abstract
Background
Immunosuppressive tumor immune microenvironment (TIME) lowers immunotherapy effectiveness. Additionally, low penetration efficiency and unpredictable drug release in tumor areas restrict tumor therapy.

Methods
A triblock copolymeric micelle (NanoPCPT+PIMDQ) was developed to carry the chemotherapeutic drug camptothecin (CPT) and the TLR7/8 agonist 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo[4,5-c] quinoline-4-amine (IMDQ) to achieve deep tumor penetration and on-demand drug release by responding to acid and reduction stimuli sequentially. The synergistic antitumour efficacy of NanoPCPT+PIMDQ was assessed both in vitro and in vivo.

Results
NanoPCPT+PIMDQ is composed of a hydrophilic PEG(polyethylene glycol) outer layer, an acid-sensitive EPEMA middle layer, and a drug inner core. Upon intratumoral injection, (i) NanoPCPT+PIMDQ first responds to the acidic tumor microenvironment and disintegrates to PIMDQ and PCPT, penetrating deep regions of the tumor; (ii) tumor cells are killed by the released CPT; (iii) DCs are activated by PIMDQ to increase the infiltration of cytotoxic T lymphocyte (CTL); and (iv) both downregulated Foxp3+ Tregs by CPT and repolarized M2 macrophages by PIMDQ can relieve the TIME.

Conclusion
This pH/GSH-responsive triblock polymer-drug conjugate reduces immunosuppression and enhances the infiltration of CTLs by codelivering CPT and IMDQ in a controllable manner, providing a promising platform for synergistic tumor chemoimmunotherapy.
Black phosphorous nanomaterials as a new paradigm for postoperative tumor treatment regimens
Authors: Hou Yanhua , Fei Yang , Liu Zehong , Liu Yingqi , Li Menghuan , Luo Zhong 
Published: August 2022

AbstractSurgery is currently a mainstream treatment modality for various solid tumor indications. However, aggressive resection of tumor tissues frequently causes postoperative complications, which severely undermine the well-being of patients. Moreover, the residue tumor cells may substantially increase the risk of local and distant tumor relapse. The recent development in black phosphorus (BP)-based nanomaterials offers a promising opportunity to address these clinical challenges. BP is an emerging nanomaterial with excellent biocompatibility and versatile functionality, which has already demonstrated great potential for a variety of biomedical applications including tumor therapy and tissue engineering. In this review, the recent advances in BP-based nanobiomaterials for the post-surgery treatment of solid tumor have been summarized, while specific emphasis was placed on their capability to continuously inhibit residue tumor growth at the surgery site as well as stimulating various healing mechanisms, aiming to preventing tumor relapse while promoting the healing of surgery-induced traumatic soft/hard tissue injuries. It is anticipated that the nanoengineered BP-based materials may open new avenues to tackle those clinical challenges in surgical treatment of solid tumors.
Investing for population mental health in low and middle income countries—where and why?
Authors: Freeman Melvyn 
Published: August 2022

Abstract
Background
Policy makers intent on improving population mental health are required to make fundamental decisions on where to invest resources to achieve optimal outcomes. While research on the effectiveness and efficiency of interventions is critical to such choices, including clinical outcomes and return on investment, in the “real world” of policy making other concerns invariably also play a role. Politics, history, community awareness and demands for care, understanding of etiology, severity of condition and local circumstances are all critical. Policy makers should not merely rely on previous allocations, but need to take active decisions regarding the proportion of resources that should be allocated to particular interventions to achieve optimum outcomes. Given that scientific evidence is only one of the reasons informing such decisions, it is necessary to have clear and informed reasons for allocations and for making cases for new mental health investments.

Main body
Investment allocations are unlikely to ever be an exact science. Alternatives therefore need to be rationally weighed up and reasoned decisions made based on this. Using prevalence data and the distribution of mental health resources in South Africa as a backdrop and proxy, investment proposals are made for LMICs with due consideration given to inter alia the social determinants of mental health, the needs and potential benefits of investments in people with severe verses common mental disorder, mental health promotion and disease prevention and to other areas that may impact on population mental health, such as management.

Conclusion
Based on a range of arguments, it is proposed that mental health investments should follow the following approach. A mental health-in-all-policies method must be adopted. There should be no more than a 20% gap in the humane and human rights oriented care, treatment and rehabilitation of people with severe mental disorder. A minimum additional amount of 10% of the amount spent on severe mental disorder should be allocated to treating people with common mental disorder. Screening for mental disabilities should take place within all chronic care services. A minimum of 3% of the budget spent on severe mental disorder should be spent on promotion and prevention programmes. An additional 1% of the allocation for severe mental disorder should be provided for managing/driving the mental health programme.
A novel 1,3,4-thiadiazole modified chitosan: synthesis, characterization, antimicrobial activity, and release study from film dressings
Authors: Mohamed Ahmad E. , Elgammal Walid E. , Dawaba Aya M. , Ibrahim Ahmed G. , Fouda Amr , Hassan Saber M. 
Published: August 2022

AbstractHerein, two new polymers designated as Cs-EATT and Cs-BATT have been synthesized via linking the chitosan with the synthesized 1,3,4-thiadiazole compounds. They were characterized using 1H,13C-NMR, FT-IR, TGA, Elemental analysis, Mass spectrum, and UV–vis spectrophotometer. The synthesized polymers exhibit high activity to control the growth of pathogenic bacteria (S. aureus, B. subtilis, E. coli, and P. aeruginosa), and unicellular fungi (C. albicans). The MIC values were in the range of 25–100 µg mL–1 for Cs-EATT and 25–200 µg mL–1 for Cs-BATT with varied clear zones. The new polymers were mixed with three film-forming agents: polyvinyl alcohol, hydroxyethyl cellulose, and carboxymethyl cellulose to form six film dressings designated as E1, E2, and E3 for Cs-EATT, and B1, B2, and B3 for Cs-BATT, respectively. The evaluation of film dressings showed that the formed films had transparency, uniformity, homogeneity, elasticity, and non-irritation pH values for skin within the normal range. The maximum percentages of Cs-E/B-ATT content were recorded for film dressings E2 and B2, with values of 92.5% and 94.9%, respectively. Also, the release percentages varied according to film dressing formulation, with values in the ranges of 83.88–93.2% for Cs-EATT and (87.7–97.35%) for Cs-EATT after 9 h.
Noonan syndrome with RAF1 gene mutations in a newborn with cerebral haemorrhage
Authors: Lan Junwei , Zeng Tianbao , Liu Sheng , Lan Juhong , Qian Lijun 
Published: August 2022

Abstract
Background
Noonan syndrome is an autosomal dominant genetic disorder that can occur in men and women and has a sporadic or family history. NS can lead to abnormal bleeding, but cerebral haemorrhage is rare. This is the first case of cerebral haemorrhage with a RAF1 gene mutation that originated in the neonatal period.

Case presentation
This case presents a newborn with a RAF1 gene mutation resulting in NS complicated with an abnormality of chromosome 46, X, del (Y) (q12). In the course of treatment, the baby's breathing suddenly increased. After an MRI examination of the skull, haemorrhaging was found in multiple parts of the brain.

Conclusions
After symptomatic treatment, the baby recovered well, but the main cause of cerebral haemorrhage was not found.
Comparing an optimised physiotherapy treatment package with usual physiotherapy care for people with tennis elbow — protocol for the OPTimisE pilot and feasibility randomised controlled trial
Authors: Bateman M. , Saunders B. , Littlewood C. , Davis D. , Beckhelling J. , Cooper K. , Skeggs A. , Foster N. E. , Vicenzino B. , Hill J. C. 
Published: August 2022

Abstract
Background
Physiotherapy is recommended for people with tennis elbow, but whilst a wide array of treatments is available, the optimal approach remains uncertain. We have therefore recently developed an optimised physiotherapy treatment package for tennis elbow based on a synthesis of the evidence, patient input and clinical consensus. It consists of detailed advice and education, a structured progressive exercise programme and provision of a counter-force elbow brace. Here, we report the protocol for our multicentre pilot and feasibility randomised controlled trial (RCT) designed to (a) examine the feasibility of our optimised physiotherapy treatment package and (b) to pilot trial processes for a future fully powered RCT to test clinical and cost-effectiveness compared with usual physiotherapy treatment.

Methods
A multicentre pilot and feasibility RCT will be conducted across three sites in England, recruiting up to 50 patients (or for a maximum of 12 months). Participants with tennis elbow, identified from physiotherapy clinic waiting lists and general practice surgeries, will be randomly allocated to receive the optimised physiotherapy treatment package or usual physiotherapy care. Analysis will focus on feasibility measures including consent rate, intervention fidelity, follow-up rate and outcome completion rate. A nested qualitative study will explore the acceptability of the study processes and patient and physiotherapist experiences of the new optimised intervention.

Discussion
This study will determine the feasibility of a new optimised physiotherapy treatment package for people with tennis elbow and pilot the processes for a future fully powered RCT. In the longer term, this treatment package may provide superior clinical outcomes for patients, in terms of pain and quality of life, and be more cost-effective for the health service.

Trial registration
Registered with the ISRCTN database 19/7/2021, https://www.isrctn.com/ISRCTN64444585
Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma
Authors: Westin Jason , Davis R. Eric , Feng Lei , Hagemeister Fredrick , Steiner Raphael , Lee Hun Ju , Fayad Luis , Nastoupil Loretta , Ahmed Sairah , Rodriguez Alma , Fanale Michelle , Samaniego Felipe , Iyer Swaminathan P. , Nair Ranjit , Oki Yasuhiro , Fowler Nathan , Wang Michael , Ma Man Chun John , Vega Francisco , McDonnell Timothy , Pinnix Chelsea , Griffith Donna , Lu Yang , Tewari Sanjit , Sun Ryan , Scott David W. , Flowers Christopher R. , Neelapu Sattva , Green Michael R. 
Published: August 2022

PURPOSE Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non–germinal center B-cell-like subset. METHODS We enrolled 60 patients with newly diagnosed non–germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322 ). Patients were treated with rituximab 375 mg/m2 intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed. RESULTS The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively. CONCLUSION Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.
Prospective Clinical Genomic Profiling of Ewing Sarcoma: ERF and FGFR1 Mutations as Recurrent Secondary Alterations of Potential Biologic and Therapeutic Relevance
Authors: Ogura Koichi , Elkrief Arielle , Bowman Anita S. , Koche Richard P. , de Stanchina Elisa , Benayed Ryma , Mauguen Audrey , Mattar Marissa S. , Khodos Inna , Meyers Paul A. , Healey John H. , Tap William D. , Hameed Meera , Zehir Ahmet , Shukla Neerav , Sawyers Charles , Bose Rohit , Slotkin Emily , Ladanyi Marc 
Published: August 2022

PURPOSE Ewing sarcoma (ES) is a primitive sarcoma defined by EWSR1-ETS fusions as the primary driver alteration. To better define the landscape of cooperating secondary genetic alterations in ES, we analyzed clinical genomic profiling data of 113 patients with ES, a cohort including more adult patients (> 18 years) and more patients with advanced stage at presentation than previous genomic cohorts. METHODS The data set consisted of patients with ES prospectively tested with the US Food and Drug Administration–cleared Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets large panel, hybrid capture-based next-generation sequencing assay. To assess the functional significance of ERF loss, we generated ES cell lines with increased expression of ERF and lines with knockdown of ERF. We assessed cell viability, clonogenic growth, and motility in these ES lines and performed transcriptomic and epigenetic analyses. Finally, we validated our findings in vivo using cell line xenografts. RESULTS Novel subsets were defined by recurrent secondary alterations in ERF, which encodes an ETS domain transcriptional repressor, in 7% of patients (five truncating mutations, one deep deletion, and two missense mutations) and in FGFR1 in another 2.7% (one amplification and two known activating mutations). ERF alterations were nonoverlapping with STAG2 alterations. In vitro, increased expression of ERF decreased tumor cell growth, colony formation, and motility in two ES cell lines, whereas ERF loss induced cellular proliferation and clonogenic growth. Transcriptomic analysis of cell lines with ERF loss revealed an increased expression of genes and pathways associated with aggressive tumor biology, and epigenetic, chromatin-based studies revealed that ERF competes with EWSR1-FLI1 at ETS-binding sites. CONCLUSION Our findings open avenues to new insights into ES pathobiology and to novel therapeutic approaches in a subset of patients with ES.
Association of ERBB2 Copy Number and Gene Coalterations With Trastuzumab Efficacy and Resistance in Human Epidermal Growth Factor Receptor 2–Positive Esophagogastric and Gastric Cancer
Authors: Hino Kaori , Nishina Tomohiro , Kajiwara Takeshi , Bando Hideaki , Nakamura Maho , Kadowaki Shigenori , Minashi Keiko , Yuki Satoshi , Ohta Takashi , Hara Hiroki , Mizukami Takuro , Moriwaki Toshikazu , Ohtsubo Koushiro , Komoda Masato , Mitani Seiichiro , Nagashima Fumio , Kato Ken , Yamada Takanobu , Hasegawa Hiroko , Yamazaki Kentaro , Yoshino Takayuki , Hyodo Ichinosuke 
Published: August 2022

PURPOSE ERBB2 copy number (CN), measured using next-generation sequencing, is a predictive biomarker for trastuzumab efficacy in human epidermal growth factor receptor 2 (HER2)–positive advanced esophagogastric and gastric cancer (AGC). We aimed to investigate the association of ERBB2 amplification and gene coalterations with response and resistance to trastuzumab-combined chemotherapy. METHODS The SCRUM-Japan GI-SCREEN was a comprehensive genomic profiling project of GI cancer tissues using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. From 885 patients with AGC who successfully underwent gene profiling, 74 with ERBB2 amplification (CN ≥ 4.0) and who received first-line trastuzumab-combined chemotherapy were selected, and ERBB2 CN and gene coalterations were assessed. RESULTS ERBB2 CN did not differ in tumor response to trastuzumab-combined chemotherapy (one-way analysis of variance test, P = .37). Multivariate analysis using the Cox proportional hazard model revealed that ERBB2 CN (continuous log2-converted CN, hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P < .01) and receptor/oncogene amplifications in the HER2 signaling pathway (hazard ratio, 2.5; 95% CI, 1.2 to 5.3; P = .01) were significant predictors for progression-free survival (PFS). ERBB2 variants coexisted in five patients (7%) and were missense mutations. Two patients with low variant allele frequencies (VAFs; 8%, 12%) showed high ERBB2 CN (55, 80) and durable response (≥ 20 months), whereas three patients with high VAFs (66%–90%) showed low ERBB2 CN (8-11) and no response with short PFS (1-10 months). CONCLUSION ERBB2 CN and gene coamplification in the HER2 signaling pathway were positive and negative predictors of PFS in trastuzumab-treated HER2-positive AGC patients, respectively. HER2-positive AGC patients with a high VAF of ERBB2 showed poor outcomes and may need HER2 tyrosine kinase inhibitors and trastuzumab deruxtecan.