bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for a phase II randomised controlled trial of TKI alone versus TKI and local consolidative radiation therapy in patients with oncogene driver-mutated oligometastatic non-small cell lung cancer
Authors: Tibdewal Anil , Agarwal JaiPrakash , Mummudi Naveen , Noronha Vanita , Prabhash Kumar , Patil Vijay , Purandare Nilendu , Janu Amit , Kaushal Rajiv , Kannan Sadhna 
Published: February 2021

IntroductionTyrosine kinase inhibitors (TKIs) have significantly improved the progression-free survival (PFS) of metastatic non-small cell lung cancer (NSCLC) with oncogene mutations of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) compared with systemic therapy alone. However, the majority eventually develop resistance with a median PFS of 8–12 months. The pattern of failure studies showed disease relapse at the original sites of the disease-harbouring resistant tumour cells.Methods and analysisThis study is designed as a phase II randomised controlled trial to evaluate the efficacy of local consolidative radiation therapy (LCRT) in addition to TKI in upfront oligometastatic NSCLC. Patients will be screened at presentation for oligometastases (≤5 sites) and will start on TKI after confirmation of EGFR or ALK mutation status. After initial TKI for 2–4 months, eligible patients will be randomised in a 1:1 ratio with stratification of oligometastatic sites (1–3 vs 4–5), performance status of 0–1 versus 2 and brain metastases. The standard arm will continue to receive TKI, and the intervention arm will receive TKI plus LCRT. Stereotactic body radiation therapy will be delivered to all the oligometastatic sites.The primary end point is PFS, and secondary end points are overall survival, local control of oligometastatic sites, toxicity and patient-reported outcomes. The sample size calculation took a median PFS of 10 months in the standard arm. To detect an absolute improvement of 7 months in the interventional arm, with a one-sided alpha of 5% and 80% power, a total of 106 patients will be accrued over a period of 48 months.Ethics and disseminationThe study is approved by the Institutional Ethics Committee II of Tata Memorial Centre, Mumbai, and registered with Clinical Trials Registry—India, CTRI/2019/11/021872, dated 5 November 2019. All eligible participants will be provided with a participant information sheet and will be required to provide written informed consent for participation in the study. The study results will be presented at a national/international conference and will be published in a peer-reviewed journal.
Uneven state distribution of homicides in Brazil and their effect on life expectancy, 2000–2015: a cross-sectional mortality study
Authors: Aburto José Manuel , Calazans Julia , Lanza Queiroz Bernardo , Luhar Shammi , Canudas-Romo Vladimir 
Published: February 2021

ObjectiveTo determine cause-specific and age-specific contributions to life expectancy changes between 2000 and 2015, separately by state and sex in Brazil, with a focus on homicides.DesignRetrospective cross-sectional demographic analysis of mortality.Setting and populationBrazilian population by age, sex and state from 2000 to 2015.Main outcome measureUsing mortality data from the Brazilian Mortality Information System and population estimates from the National Statistics Office, we used death distribution methods and the linear integral decomposition model to estimate levels and changes in life expectancy. We also examine how multiple causes of death, including those attributable to homicides and amenable/avoidable mortality, contributed to these changes from 2000 to 2015.ResultsBetween 2000 and 2015, life expectancy in Brazil increased from 71.5 to 75.1 years. Despite state-level variation in gains, life expectancy increased in almost all states over this period. However across Brazil, homicide mortality contributed, to varying degrees, to either attenuated or decreased male life expectancy gains. In Alagoas in 2000–2007 and Sergipe in 2007–2015, homicides contributed to a reduction in life expectancy of 1.5 years, offsetting gains achieved through improvements due to medically amenable causes. In the period 2007–2015, male life expectancy could have been improved by more than half a year in 12 of Brazil’s states if homicide mortality had remained at the levels of 2007.ConclusionsHomicide mortality appears to offset life expectancy gains made through recent improvements to mortality amenable to medical services and public health interventions, with considerable subnational heterogeneity in the extent of this phenomenon. Efforts combating the causes of homicides can increase life expectancy beyond what has been achieved in recent decades.
The interactive effects of stream temperature, stream size, and non-native species on Yellowstone cutthroat trout
Authors: Al-Chokhachy Robert , Lien Mike , Shepard Bradley B. , High Brett 
Published: February 2021

Climate change and non-native species are considered two of the biggest threats to native salmonids in North America. We evaluated how non-native salmonids and stream temperature and discharge were associated with Yellowstone cutthroat trout (Oncorhynchus clarkii bouvieri) distribution, abundance, and body size to gain a more complete understanding of the existing threats to native populations. Allopatric Yellowstone cutthroat trout were distributed across a wide range of average August temperatures (3.2 to 17.7 °C), but occurrence significantly declined at colder temperatures (<10 °C) with increasing numbers of non-natives. At warmer temperatures, occurrence remained high, despite sympatry with non-natives. Yellowstone cutthroat trout relative abundance was significantly reduced with increasing abundance of non-natives, with the greatest impacts at colder temperatures. Body sizes of large Yellowstone cutthroat trout (90th percentile) significantly increased with warming temperatures and larger stream size, highlighting the importance of access to these more productive stream segments. Considering multiple population-level attributes demonstrates the complexities of how native salmonids (such as Yellowstone cutthroat trout) are likely to be affected by shifting climates.
Comparisons of One to Three Monthly Injections of Aflibercept for Diabetic Macular Edema by Practical Protocol
Authors: Hayashi Yuko , Tatsumi Tomoaki , Oshitari Toshiyuki , Kaiho Tomomi , Takatsuna Yoko , Arai Miyuki , Baba Takayuki , Yamamoto Shuichi 
Published: February 2021

The purpose of this study was to compare the efficacies of one initial intravitreal injection of aflibercept followed by a pro re nata (PRN; 1+PRN) regimen to those of three consecutive monthly injections followed by the PRN (3+PRN) regimen for diabetic macular edema (DME) with practical protocols. The medical records of 95 eyes of 71 cases that were diagnosed with DME and had received intravitreal aflibercept (IVA) injections were reviewed. Fifty-seven eyes had received IVA with the 1+PRN regimen, and 38 eyes had received IVA with the 3+PRN regimen. The best-corrected visual acuity (BCVA) and the central macular thickness (CMT) were measured at the baseline and at 1, 3, 6, and 12 months after the IVA. The mean number of injections of the 1+PRN group was

2.9
±
1.7

, which was significantly fewer than that of the 3+PRN group at

4.6
±
1.4

(

P
<
0.001

). The change of the mean BCVA before and after the IVA at 12 months of the 3+PRN group was

−
0.14
±
0.17

logMAR units which was significantly better than that of the 1+PRN group of

−
0.045
±
0.25

logMAR units (

P
=
0.02

). The change of the CMT before and after the IVA at 6 months of the 3+PRN group was

−
141.3
±
152.4

μ
m

which was significantly more than that of the 1+PRN group at

−
86.1
±
117.8

μ
m

(

P
=
0.013

). Although the mean number of injections was more than that in the 1+PRN regimen, the 3+PRN regimen had better visual outcomes at 12 months. In a practical protocol, we recommend the 3+PRN regimen for patients with DME (IRB#3541).
Reproductive Diseases and Disorders of Female Camels: An Assessment and Pathological and Bacteriological Study in Eastern Ethiopia
Authors: Belina Dinaol , Eshetu Amare , Alemu Sisay , Shasho Bekyad , Mohammed Tajudin , Mohammed Ahmedin , Mummed Bahar , Regassa Dereje 
Published: February 2021

Camels are the most efficient domesticated animals in arid and semiarid areas of the world. In Ethiopia, they are the main livestock kept to sustain the livelihoods of pastoralists, as camels are used for milk and meat production and also for transportation. However, she-camel reproductive diseases are one of the major constraints for camel-producing communities. A cross-sectional study was conducted from November 2018 to December 2019 to identify and characterize pathological lesions and isolate possible bacteria associated with reproductive diseases and disorders in she-camels slaughtered at Dire Dawa and Babille municipal abattoirs. A total of 155 study animals were examined by recruiting all she-camels slaughtered during every abattoir visit. Overall, 562 reproductive organs, the ovaries, oviducts, uterus, and cervix, were examined through observation, palpation, and incision, and the animal- and organ-level pathological lesion prevalence were found to be 29% and 64.6%, respectively. Degenerative changes, inflammatory lesions (endometritis and salpingitis), growth disturbances (e.g., ovarian hypoplasia), and noninflammatory lesions (e.g., noninflammatory edema) were the identified pathological lesions. Occurrences of pathological changes among reproductive organs had differences where significantly the highest proportion (

p

= 0.00) was observed in the uteri. Of the 119 microbiological samples processed, 77.3% were positive for single or mixed bacterial genera, from which 7 different bacterial isolates and 14 other unidentified Gram-negative bacteria were detected. E. coli, Salmonella, and Staphylococcus spp. were the most frequently isolated organisms with 28.2%, 26.9%, and 12.8% frequencies, respectively. The result of the questionnaire survey showed 74% of the respondents had culled the she-camel at productive age because of poor reproductive performance associated with refused mating, abortion, and repeat breeding (poor conception). On the other hand, a majority of camel herders had poor to no information and access to modern veterinary services; nevertheless, they had good indigenous knowledge on how to manage reproductive abnormalities. Considering the importance of camels in our study area, further research on camel reproductive diseases and abnormalities with wider sample and epidemiology need to be conducted using molecular and hormonal assay techniques.
Prognostic Implications of ALDH1 and Notch1 in Different Subtypes of Oral Cancer
Authors: de Freitas Filho Silas Antonio Juvencio , Coutinho-Camillo Cláudia Malheiros , Oliveira Katia Klug , Bettim Bárbara Beltrame , Pinto Clóvis Antônio Lopes , Kowalski Luiz Paulo , Oliveira Denise Tostes 
Published: February 2021

Background. The present study aimed to investigate the clinical significance and prognostic value of the immunoexpression of cancer stem cell markers, ALDH1 and Notch1, in subtypes of oral squamous cell carcinoma. Materials and Methods. The expression of ALDH1 and Notch1 in 63 patients with well and poorly differentiated oral squamous cell carcinomas and their subtypes, verrucous carcinoma and basaloid squamous cell carcinoma, was evaluated by immunohistochemistry. The semi-quantitative analysis of the ALDH1 and Notch immunoexpression levels, based on the capture of 10 microscopic fields, at 400X magnification, at the invasive tumor front was performed and associated with clinicopathological variables using the chi-square test or Fisher’s exact test. The overall and disease-free survival rates were estimated according to the Kaplan–Meier method and the curves were compared using the log-rank test. The independent effects of variables were calculated using Cox’s proportional hazards regression model. Results. Strong ALDH1 and Notch1 expression was observed in 16 (25.4%) and 27 (42.9%) oral squamous cell carcinomas including their subtypes, respectively. Most tumors with strong immunoexpression of ALDH1 were basaloid squamous cell carcinoma (56.3%). Statistically significant associations were observed between the strong immunoexpression of Notch1 in poorly differentiated oral squamous cell carcinoma with perineural infiltration (

p

= 0.011) and lymph node involvement (pN+) (

p

= 0.034). The strong immunoexpression of ALDH1 was a prognostic factor associated with worse overall survival (

p

= 0.040) for patients with oral cancer. Conclusion. The strong immunoexpression of Notch1 can contribute to identification of patients with poorly differentiated oral squamous cell carcinoma, who have perineural infiltration or lymph node metastasis. In addition, the strong immunoexpression of ALDH1 may help to identify a worse prognosis in patients with oral squamous cell carcinoma and their subtypes.
Clinical Utility of Preoperative Vitamin D3 Injection for Preventing Transient Hypocalcemia after Total Thyroidectomy
Authors: Kim Kwangsoon , Lee Cho Rok , Kang Sang-Wook , Lee Jandee , Jeong Jong Ju , Nam Kee-Hyun , Chung Woong Youn 
Published: February 2021

Background. Postoperative transient hypocalcemia (TH) is a common complication of total thyroidectomy. This retrospective study evaluated the clinical utility of preoperative vitamin D3 injection for the prevention of TH after total thyroidectomy. Methods. We included 2294 patients who underwent total thyroidectomy from January 2015 until October 2018 and retrospectively analyzed their data by complete chart review at our hospital. The patients were divided into two groups: vitamin D3 injection (VDI; n = 342) and vitamin D3 noninjection (VDN; n = 1952). TH was defined as serum calcium <8.2 mg/dL and signs or symptoms of hypocalcemia. Results. The mean preoperative serum 25-hydroxyvitamin D (25-OHD) levels of the VDI group were significantly lower than those of the VDN group (16.5 ± 6.9 ng/mL vs 19.4 ± 8.7 ng/mL,

p

< 0.001). Multivariate analysis indicated that the significant risk factors of TH include vitamin D noninjection (hazard ratio (HR): 1.717, 95% confidence interval (CI): 1.282–2.300,

p

< 0.001), male gender (HR: 1.427, 95% CI: 1.117–1.822,

p

= 0.004), and capsular extension (HR: 1.273, 95% CI: 1.011–1.603,

p

= 0.040). Conclusions. Preoperative vitamin D3 injection significantly contributed to the prevention of TH after total thyroidectomy. Further prospective or multicenter studies must be conducted to determine the effect of vitamin D3 injection.
How Epigenetic Therapy Beats Adverse Genetics in Monosomy Karyotype AML
Authors: O'Hagan Heather M. , Rassool Feyruz V. , Nephew Kenneth P. 
Published: February 2021

Abstract
The study by Greve and colleagues, in this issue of Cancer Research, provides new molecular insights into the intriguing clinical activity of DNA hypomethylating agents (HMA) in patients with acute myeloid leukemia (AML) with monosomal karyotypes. Patients with AML with adverse monosomal karyotypes are known to benefit from HMAs, but not cytarabine, a cytidine analog without HMA activity, but the specific molecular mechanisms remain poorly understood. The authors investigated the mechanistic effects of HMAs on gene reactivation in AML in the context of the most common monosomal karyotypes, genetic deletion of chromosome 7q and 5q. They identified genes with tumor-suppressive properties, an endogenous retrovirus cooperatively repressed by DNA hypermethylation, and increased genetic losses on hemizygous chromosomal regions versus normal biallelic regions in AML cell models. Treatment with HMAs preferentially induced expression of these hemizygous genes to levels similar to those of genes in a biallelic state. In addition to CpG hypomethylation, decitabine treatment resulted in histone acetylation and an open chromatin configuration specifically at hemizygous loci. By using primary blood blasts isolated from patients with AML receiving decitabine and AML patient-derived xenograft models established from patients with either monosomal karyotypes or normal cytogenetics, Greve and colleagues both validated their findings in primary patient samples and demonstrated superior antileukemic activity of decitabine compared with chemotherapy with cytarabine. These mechanistic insights into how epigenetic therapy beats adverse genetics in monosomy karyotype AML will open new therapeutic opportunities for a difficult-to-treat patient group.
See related article by Greve et al., p. 834
Abstract PS16-22: Targeting resistance to current CDK4/6 therapies by RGT-419B, an inhibitor with optimized kinase activity spectrum
Authors: Xie Zhi , Han Jing , Hu Zhilong , He Hu , Sun Xianqiang , Zhang Fei , Lin Jing , Yao Lili , Wang Xinjuan , Mei Liufeng , Liu Yangyang , Zhu Guoyun , Chen Xi , Zhu Xiaotian , Zhong Wenge 
Published: February 2021

Abstract
Cyclin-dependent kinases (CDKs) 4/6 inhibitors are a powerful class of therapeutic drugs for the treatment of advanced metastatic breast cancer. However, the currently approved CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have dose-limiting toxicities that require treatment holidays or reductions to sub-optimal doses, thus limiting full target inhibition. The residual CDK4/6 activity, together with persistent signaling through CDK2/cyclin E are among key resistant mechanisms that can compromise full clinical benefit. RGT-419B is a 3rd generation CDK inhibitor with an optimized kinase activity spectrum that has been discovered employing a Computer Accelerated Rational Design technology platform. RGT-419B has potent sub-nM CDK4 activity with desired degrees of selectivity against kinases such as CDK6, CDK9 and GSK3β to enable full target engagement with an improved safety profile. Furthermore, single digit nM CDK2 kinase activity has been incorporated into the design of RGT-419B to combat Cyclin E/CDK2-driven resistance. In vitro, RGT-419B showed more robust activity against palbociclib-resistant ER+ breast cancer cells than abemaciclib. In ER+ T47D breast cancer cells with overexpression of Cyclin E1, RGT-419B exhibited better antiproliferation activity than either abemaciclib or palbociclib. RGT-419B also demonstrated more durable in vivo tumor growth inhibition when compared with abemaciclib in an ER+ breast cancer xenograft model. The optimized kinase activity spectrum of RGT-419B provides an opportunity to treat ER+ breast cancer patients refractory to the existing CDK4/6 inhibitors, as either a single agent or in combination with other therapies.
Citation Format: Zhi Xie, Jing Han, Zhilong Hu, Hu He, Xianqiang Sun, Fei Zhang, Jing Lin, Lili Yao, Xinjuan Wang, Liufeng Mei, Yangyang Liu, Guoyun Zhu, Xi Chen, Xiaotian Zhu, Wenge Zhong. Targeting resistance to current CDK4/6 therapies by RGT-419B, an inhibitor with optimized kinase activity spectrum [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-22.
Abstract PS17-31: Investigating the estrogen receptor Y537S mutation in transgenic models of luminal B breast cancer
Authors: Johnson Gabriella , Roccamo Joshua , Lavoie Cynthia , Zuo Dongmei , Sanguin-Gendreau Virginie , Lee Adrian , Li Zheqi , Oesterreich Steffi , Muller William 
Published: February 2021

Abstract
Breast cancer is the most prevalent cancer in women and over two-thirds of cases express the estrogen receptor (ER). Significantly, metastatic ER positive breast cancer is the leading cause of breast cancer mortality. Despite the success of endocrine therapy to treat ER-positive breast cancers, resistance to treatment is a major problem and relapse commonly occurs though patients initially respond well to treatment. The ER Y537S mutant represents one of the most common gain-of-function mutations detected in the metastatic biopsies of patients with ER-positive breast cancer. Previous in-vitro analyses have shown that the ER Y537S mutant exhibits enhanced ER transcriptional activity by adopting a ligand-independent agonist confirmation. In our study, we seek to provide a deeper understanding of the role of this mutant by modeling the human ER Y537S mutant (ER Y541S in mice). Our lab has generated a Cre-inducible knock-in mouse model expressing the activating point mutation driven by the endogenous ER promoter, and it has been shown that when expressed ubiquitously the mutated ER leads to dramatic developmental effects. In order to further our observations in the context of endocrine resistant metastatic breast cancer, we characterize mamary tumour growth of the ER Y541S mutant in combination with luminal B models of mammary tumourigenesis. Consistent with the notion that these ER mutations occur seldom in primary tumours, preliminary data shows that tumour onset and tumour outgrowth is unaffected by the activating point mutation. When analysing tumours from both ER mutant and wildtype ER control animals, it was found that tumours with mutant ER display more basal-like cytokeratins at the RNA level via RNA sequencing and at the protein level via immunohistochemistry. This expression pattern is often associated with poorer prognosis in the clinic. Through ongoing analyses, we also seek to better understand our model through tumour regression studies (doxycycline withdrawal), treatment with tamoxifen and blocking the main source of estrogens via ovariotomies. By studying the ER Y537S mutation in models of luminal B breast cancer, we hope to investigate the factors leading to tumour recurrence and provide a deeper understanding of potential escape pathways to therapy.
Citation Format: Gabriella Johnson, Joshua Roccamo, Cynthia Lavoie, Dongmei Zuo, Virginie Sanguin-Gendreau, Adrian Lee, Zheqi Li, Steffi Oesterreich, William Muller. Investigating the estrogen receptor Y537S mutation in transgenic models of luminal B breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-31.
PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability
Authors: Pitarresi Jason R. , Norgard Robert J. , Chiarella Anna M. , Suzuki Kensuke , Bakir Basil , Sahu Varun , Li Jinyang , Zhao Jun , Marchand Benoît , Wengyn Maximilian D. , Hsieh Antony , Kim Il-Kyu , Zhang Amy , Sellin Karine , Lee Vivian , Takano Shigetsugu , Miyahara Yoji , Ohtsuka Masayuki , Maitra Anirban , Notta Faiyaz , Kremer Richard , Stanger Ben Z. , Rustgi Anil K. 
Published: February 2021

Abstract

Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone–related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in patients with pancreatic cancer. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in pancreatic ductal adenocarcinoma metastases. Loss of PTHrP—either genetically or pharmacologically—dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the ability of tumor cells to initiate metastatic cascade. Spp1, which encodes osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability.

Significance:
Pancreatic cancer often presents with metastases, yet no strategies exist to pharmacologically inhibit this process. Herein, we establish the oncogenic and prometastatic roles of PTHLH, a novel amplified gene in pancreatic ductal adenocarcinoma. We demonstrate that blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice.
This article is highlighted in the In This Issue feature, p. 1601