bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secondary resistance to anti-EGFR therapy by transcriptional reprogramming in patient-derived colorectal cancer models
Authors: Vangala Deepak , Ladigan Swetlana , Liffers Sven T. , Noseir Soha , Maghnouj Abdelouahid , Götze Tina-Maria , Verdoodt Berlinda , Klein-Scory Susanne , Godfrey Laura , Zowada Martina K. , Huerta Mario , Edelstein Daniel L. , de Villarreal Jaime Martinez , Marqués Miriam , Kumbrink Jörg , Jung Andreas , Schiergens Tobias , Werner Jens , Heinemann Volker , Stintzing Sebastian , Lindoerfer Doris , Mansmann Ulrich , Pohl Michael , Teschendorf Christian , Bernhardt Christiane , Wolters Heiner , Stern Josef , Usta Selami , Viebahn Richard , Admard Jacob , Casadei Nicolas , Fröhling Stefan , Ball Claudia R. , Siveke Jens T. , Glimm Hanno , Tannapfel Andrea , Schmiegel Wolff , Hahn Stephan A. 
Published: July 2021

Abstract
Background
The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms.

Methods
We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways.

Results
In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies.

Conclusions
Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.
RETRACTED ARTICLE: Mesenchymal stem cells ameliorate renal fibrosis by galectin-3/Akt/GSK3β/Snail signaling pathway in adenine-induced nephropathy rat
Authors: Tang Huajun , Zhang Peiyue , Zeng Lianlin , Zhao Yu , Xie Libo , Chen Bo 
Published: July 2021

Abstract
Background
Tubulointerstitial fibrosis (TIF) is one of the main pathological features of various progressive renal damages and chronic kidney diseases. Mesenchymal stromal cells (MSCs) have been verified with significant improvement in the therapy of fibrosis diseases, but the mechanism is still unclear. We attempted to explore the new mechanism and therapeutic target of MSCs against renal fibrosis based on renal proteomics.

Methods
TIF model was induced by adenine gavage. Bone marrow-derived MSCs was injected by tail vein after modeling. Renal function and fibrosis related parameters were assessed by Masson, Sirius red, immunohistochemistry, and western blot. Renal proteomics was analyzed using iTRAQ-based mass spectrometry. Further possible mechanism was explored by transfected galectin-3 gene for knockdown (Gal-3 KD) and overexpression (Gal-3 OE) in HK-2 cells with lentiviral vector.

Results
MSCs treatment clearly decreased the expression of α-SMA, collagen type I, II, III, TGF-β1, Kim-1, p-Smad2/3, IL-6, IL-1β, and TNFα compared with model rats, while p38 MAPK increased. Proteomics showed that only 40 proteins exhibited significant differences (30 upregulated, 10 downregulated) compared MSCs group with the model group. Galectin-3 was downregulated significantly in renal tissues and TGF-β1-induced rat tubular epithelial cells and interstitial fibroblasts, consistent with the iTRAQ results. Gal-3 KD notably inhibited the expression of p-Akt, p-GSK3β and snail in TGF-β1-induced HK-2 cells fibrosis. On the contrary, Gal-3 OE obviously increased the expression of p-Akt, p-GSK3β and snail.

Conclusion
The mechanism of MSCs anti-renal fibrosis was probably mediated by galectin-3/Akt/GSK3β/Snail signaling pathway. Galectin-3 may be a valuable target for treating renal fibrosis.
Assessment of changes in autophagic vesicles in human immune cell lines exposed to nano particles
Authors: David Christopher A. W. , del Castillo Busto M. Estela , Cuello-Nuñez Susana , Goenaga-Infante Heidi , Barrow Michael , Fernig David G. , Murray Patricia , Rosseinsky Matthew J. , Owen Andrew , Liptrott Neill J. 
Published: July 2021

Abstract
Background
Safe and rational development of nanomaterials for clinical translation requires the assessment of potential biocompatibility. Autophagy, a critical homeostatic pathway intrinsically linked to cellular health and inflammation, has been shown to be affected by nanomaterials. It is, therefore, important to be able to assess possible interactions of nanomaterials with autophagic processes.

Results
CEM (T cell), Raji (B lymphocyte), and THP-1 (human monocyte) cell lines were subject to treatment with rapamycin and chloroquine, known to affect the autophagic process, in order to evaluate cell line-specific responses. Flow cytometric quantification of a fluorescent autophagic vacuole stain showed that maximum observable effects (105%, 446%, and 149% of negative controls) were achieved at different exposure durations (8, 6, and 24 h for CEM, Raji, and THP-1, respectively). THP-1 was subsequently utilised as a model to assess the autophagic impact of a small library of nanomaterials. Association was observed between hydrodynamic size and autophagic impact (r2 = 0.11, p = 0.004). An ELISA for p62 confirmed the greatest impact by 10 nm silver nanoparticles, abolishing p62, with 50 nm silica and 180 nm polystyrene also lowering p62 to a significant degree (50%, 74%, and 55%, respectively, p < 0.05).

Conclusions
This data further supports the potential for a variety of nanomaterials to interfere with autophagic processes which, in turn, may result in altered cellular function and viability. The association of particle size with impact on autophagy now warrants further investigation.

Graphic abstract
New criteria for selecting reliable Thellier-type paleointensity results from the 1960 Kilauea lava flows, Hawaii
Authors: Jeong Doohee , Liu Qingsong , Yamamoto Yuhji , Yu Yongjae , Zhao Xiang , Qin Huafeng 
Published: July 2021

AbstractThellier-type paleointensity experiments associated with partial thermal remanent magnetization checks have been widely used to determine paleointensity values from volcanic and archaeological media. However, previous studies have revealed that a substantial portion of paleointensity results with positive checks for historical lava samples largely fails to predict known Earth magnetic field intensity values. To determine the fidelity of paleointensity values, conventional Thellier-type paleointensity experiments were performed on Kilauea lava flows that erupted in 1960. The positive partial thermal remanent magnetization checks for our results range from 30.28 ± 1.38 µT to 52.94 ± 1.89 µT. This strongly indicates that conventional paleointensity checks cannot guarantee the fidelity of paleointensity results, especially when the unblocking temperatures for the newly formed magnetic particles are higher than the treatment temperature. Therefore, in this study, to check for thermal alteration during heating, the temperature dependence of the hysteresis parameter measured at room temperature for the thermally treated samples was also measured. Our new results show that nearly all biased paleointensity values correspond to a ratio of the coercivity of remanence to the magnetic coercivity of > 3 and a chemical alteration index > ~ 10%, which indicates the strong effect of the domain state and thermal alteration on the fidelity of the paleointensity results. Our study provides feasible criteria to further improve the fidelity of paleointensity estimations.
Relationship between the structure and function of the transcriptional regulator E2A
Authors: Liang Jia-Jie , Peng Hu , Wang Jiao-Jiao , Liu Xiao-Hui , Ma Lan , Ni Yi-Ran , Yang Huai-Jie , Zhang Yan-Qiong , Ai Wen-Bing , Wu Jiang-Feng 
Published: July 2021

AbstractE proteins are transcriptional regulators that regulate many developmental processes in animals and lymphocytosis and leukemia in Homo sapiens. In particular, E2A, a member of the E protein family, plays a major role in the transcriptional regulatory network that promotes the differentiation and development of B and T lymphocytes. E2A-mediated transcriptional regulation usually requires the formation of E2A dimers, which then bind to coregulators. In this review, we summarize the mechanisms by which E2A participates in transcriptional regulation from a structural perspective. More specifically, the C-terminal helix-loop-helix (HLH) region of the basic HLH (bHLH) domain first dimerizes, and then the activation domains of E2A bind to different coactivators or corepressors in different cell contexts, resulting in histone acetylation or deacetylation, respectively. Then, the N-terminal basic region (b) of the bHLH domain binds to or dissociates from a specific DNA motif (E-box sequence). Last, trans-activation or trans-repression occurs. We also summarize the properties of these E2A domains and their interactions with the domains of other proteins. The feasibility of developing drugs based on these domains is discussed.
Complete closure of a colo-duodenal fistula in a patient with advanced ascending colon cancer after pembrolizumab combined with radiation therapy: a case report
Authors: Tominaga Tetsuro , Nonaka Takashi , Fukuda Akiko , Moriyama Masaaki , Oyama Shosaburo , Ishii Mitsutoshi , Nishimuta Masato , Fujise Yuta , Sawai Terumitsu , Nagayasu Takeshi 
Published: July 2021

Abstract
Background
A colo-duodenal fistula is a very rare complication of colon cancer that presents with not only severe clinical symptoms, but a poor prognosis due to locally advanced cancer. A novel immune checkpoint inhibitor for colon cancer patients provides a high objective response rate. Recently, radiation therapy combined with immune checkpoint inhibitor therapy has been reported to have a synergistic antitumor effect. A case of complete closure of a colo-duodenal fistula in a patient with locally advanced colon cancer after combined pembrolizumab and radiation therapy is reported.

Case presentation
A 66-year-old man presented with abdominal distention. Abdominal contrast-enhanced computed tomography (CT) showed a 80-mm bulky mass in the right upper quadrant. The tumor created a fistula to the second portion of the duodenum. Upper gastrointestinal endoscopy showed a colo-duodenal fistula. Gastro-jejunal bypass and ileostomy were performed to prevent bowel obstruction, followed by systemic chemotherapy. MSI-high was diagnosed on examination of the biopsy specimen. Treatment was then changed to immunotherapy using pembrolizumab; after six courses, the tumor markers were decreased to within normal ranges, but the main tumor increased. Radiation therapy was then given for local control of the main tumor, after which CT showed that all of the tumor, including the main tumor, lymph node metastases, and the colo-duodenal fistula, had gradually shrunk. Follow-up upper gastrointestinal endoscopy showed that the colo-duodenal fistula had closed completely. PET–CT showed no abnormal uptake in all tumors, and clinical complete response was diagnosed. Now, 21 months after diagnosis, the tumor is well controlled without evidence of regrowth.

Conclusions
Pembrolizumab combined with radiation therapy has a potentially dramatic therapeutic effect for advanced colon cancer.
Acute mental health presentations before and during the COVID-19 pandemic
Authors: Mukadam Naaheed , Sommerlad Andrew , Wright Jessica , Smith Abigail , Szczap Aleksandra , Solomou Solomis , Bhome Rohan , Thayalan Roshan , Abrol Esha , Aref-Adib Golnar , Maconick Lucy , Aubrey-Jones Dominic , Tugrul Senem , Knowles Melanie , Menys Helen , Sathanandan Shivanthi , Moslehi Sarah , Huntley Jonathan , Liu Kathy , Carlos Bazo-Alvarez Juan 
Published: July 2021

Background
A number of community based surveys have identified an increase in psychological symptoms and distress but there has been no examination of symptoms at the more severe end of the mental health spectrum.

Aims
We aimed to analyse numbers and types of psychiatric presentations to inform planning for future demand on mental health services in light of the COVID-19 pandemic.

Method
We analysed electronic data between January and April 2020 for 2534 patients referred to acute psychiatric services, and tested for differences in patient demographics, symptom severity and use of the Mental Health Act 1983 (MHA), before and after lockdown. We used interrupted time-series analyses to compare trends in emergency department and psychiatric presentations until December 2020.

Results
There were 22% fewer psychiatric presentations the first week and 48% fewer emergency department presentations in the first month after lockdown initiated. A higher proportion of patients were detained under the MHA (22.2 v. 16.1%) and Mental Capacity Act 2005 (2.2 v. 1.1%) (χ2(2) = 16.3, P < 0.0001), and they experienced a longer duration of symptoms before seeking help from mental health services (χ2(3) = 18.6, P < 0.0001). A higher proportion of patients presented with psychotic symptoms (23.3 v. 17.0%) or delirium (7.0 v. 3.6%), and fewer had self-harm behaviour (43.8 v. 52.0%, χ2(7) = 28.7, P < 0.0001). A higher proportion were admitted to psychiatric in-patient units (22.2 v. 18.3%) (χ2(6) = 42.8, P < 0.0001) after lockdown.

Conclusions
UK lockdown resulted in fewer psychiatric presentations, but those who presented were more likely to have severe symptoms, be detained under the MHA and be admitted to hospital. Psychiatric services should ensure provision of care for these patients as well as planning for those affected by future COVID-19 waves.
Real-World Data on Adult T-Cell Leukemia/Lymphoma in Latin America: A Study From the Grupo de Estudio Latinoamericano de Linfoproliferativos
Authors: Malpica Luis , Enriquez Daniel J. , Castro Denisse A. , Peña Camila , Idrobo Henry , Fiad Lorena , Prates Maria , Otero Victoria , Biglione Mirna , Altamirano Milagros , Sandival-Ampuero Gustavo , Aviles-Perez Ursula , Meza Kelly , Aguirre-Martinez Laura , Cristaldo Nancy , Maradei Juan L. , Guanchiale Luciana , Soto Pablo , Viñuela Jose L. , Cabrera Maria E. , Paredes Sally Rose , Riva Eloisa , Di Stefano Marcos , Noboa Andrea , Choque Juan A. , Candelaria Myrna , Von Glasenapp Alana , Valvert Fabiola , Torres-Viera Maria A. , Castillo Jorge J. , Ramos Juan Carlos , Villela Luis , Beltran Brady E. 
Published: July 2021

PURPOSE Adult T-cell leukemia/lymphoma (ATLL) is an aggressive disease caused by the human T-cell leukemia virus type 1. Real-world data of ATLL in Latin America are lacking. PATIENTS AND METHODS We analyzed patients with ATLL (acute, lymphomatous, chronic, and smoldering) encountered in 11 Latin American countries between 1995 and 2019. Treatment response was assessed according to the 2009 consensus report. Survival curves were estimated using the Kaplan-Meier method and log-rank test. RESULTS We identified 253 patients; 226 (lymphomatous: n = 122, acute: n = 73, chronic: n = 26, and smoldering: n = 5) had sufficient data for analysis (median age 57 years). Most patients with ATLL were from Peru (63%), Chile (17%), Argentina (8%), and Colombia (7%). Hypercalcemia was positively associated with acute type (57% v lymphomatous 27%, P = .014). The median survival times (months) were 4.3, 7.9, 21.1, and not reached for acute, lymphomatous, chronic, and smoldering forms, with 4-year survival rates of 8%, 22%, 40%, and 80%, respectively. First-line zidovudine (AZT)-interferon alfa (IFN) resulted in an overall response rate of 63% (complete response [CR] 24%) for acute. First-line chemotherapy yielded an overall response rate of 41% (CR 29%) for lymphomatous. CR rate was 42% for etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone versus 12% for cyclophosphamide, vincristine, doxorubicin, and prednisone–like regimen ( P < .001). Progression-free survival at 1 year for acute type patients treated with AZT-IFN was 67%, whereas 2-year progression-free survival in lymphomatous type patients who achieved CR after chemotherapy was 77%. CONCLUSION This study confirms Latin American ATLL presents at a younger age and has a high incidence of lymphomatous type, low incidence of indolent subtypes, and worse survival rates as compared with Japanese patients. In aggressive ATLL, chemotherapy remains the preferred choice for lymphomatous favoring etoposide-based regimen (etoposide, cyclophosphamide, vincristine, doxorubicin, and prednisone), whereas AZT-IFN remains a good first-line option for acute subtype.
Rising Inequality in Mothers' Employment Statuses: The Role of Intergenerational Transmission
Authors: Binder Ariel J. 
Published: July 2021

AbstractDuring the late twentieth century, U.S. mothers' propensities to hold full-time jobs became increasingly unequal across the distribution of socioeconomic status (SES). Consequently, daughters in high-SES households became more likely to be raised by working mothers than daughters in low-SES households. To what extent did this unequal exposure further shape maternal employment inequality in the twenty-first century—when these daughters had grown into adults and begun to raise their own children? Leveraging the genealogical structure of the Panel Study of Income Dynamics, this article estimates intergenerational employment coefficients on a sample of late twentieth century mothers and their daughters. It documents a much stronger intergenerational relationship in high-SES families than in low-SES families. Supplementary analyses reveal that being raised by a working mother significantly reduces the motherhood employment penalty among high-SES women but not among low-SES women. Unequal rates of mother-daughter employment transmission by SES can account for 36% of growing inequality in maternal employment across SES groups, observed in the Current Population Survey, between 1999 and 2016. These findings indicate that family-level transmission processes magnify the effects of structural forces on maternal employment inequality.
Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study: A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments
Authors: Habota Tina , Sandu Anca-Larisa , Waiter Gordon D. , McNeil Christopher J. , Steele J. Douglas , Macfarlane Jennifer A. , Whalley Heather C. , Valentine Ruth , Younie Dawn , Crouch Nichola , Hawkins Emma L. , Hirose Yoriko , Romaniuk Liana , Milburn Keith , Buchan Gordon , Coupar Tessa , Stirling Mairi , Jagpal Baljit , MacLennan Beverly , Priba Lucasz , Harris Mathew A. , Hafferty Jonathan D. , Adams Mark J. , Campbell Archie I. , MacIntyre Donald J. , Pattie Alison , Murphy Lee , Reynolds Rebecca M. , Elliot Rebecca , Penton-Voak Ian S. , Munafò Marcus R. , Evans Kathryn L. , Seckl Jonathan R. , Wardlaw Joanna M. , Lawrie Stephen M. , Haley Christopher S. , Porteous David J. , Deary Ian J. , Murray Alison D. , McIntosh Andrew M. 
Published: July 2021

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables; physical measures; questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder; laboratory samples; cognitive tests; and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures relevant to the study of depression, psychological resilience, and cognition. In addition, routinely collected historic NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.
Sexual disorders in the men treated in a psychiatric ward
Authors: Błachut Michał , Badura-Brzoza Karina , Ścisło Piotr , Bugdol Monika , Świerzy Krzysztof , Piegza Magdalena , Gorczyca Piotr 
Published: July 2021

Cel pracyPróba oceny wpływu podwójnej diagnozy na występowanie zaburzeń seksualnych oraz ocena problemów z funkcjonowaniem seksualnym mężczyzn leczonych w oddziale psychiatrycznym.MetodaW badaniu udział wzięło 140 mężczyzn hospitalizowanych psychiatrycznie (średnia wieku 40,4 ±12,7 lat) z rozpoznaniem schizofrenii, zaburzeń afektywnych, lękowych, uzależnień oraz podwójnej diagnozy (schizofrenii i uzależnienia). W badaniach użyto Kwestionariusza Seksuologicznego Kokoszki oraz Międzynarodowego Indeksu Funkcji Seksualnych IIEF-5.WynikiWystępowanie zaburzeń seksualnych w badanej grupie notowano u 83.6% pacjentów. Najczęściej obserwowano obniżenie potrzeb seksualnych (53.6%) i opóźnienie orgazmu (40%). Zaburzenia erekcji w zależności od zastosowanego narzędzia badawczego pojawiły się u 38.6% badanych (wg Kwestionariusza Kokoszki) i 61.4% badanych (IIEF-5). Ciężkie zaburzenia erekcji występowały częściej w grupie chorych nie posiadających partnera (12.4% vs 0; p=0.000) w porównaniu do osób w związkach oraz w grupie z zaburzeniami lękowymi (p=0.028) w porównaniu do grup z innymi zaburzeniami psychicznymi. W grupie osób z podwójną diagnozą (PD) zaburzenia seksualne obserwowano częściej w porównaniu do chorych na schizofrenię (p=0.034). Leczenie powyżej 5 lat wiązało się częściej z występowaniem zaburzeń seksualnych (p=0,007). W grupie PD brak orgazmu i nadmierne potrzeby seksualne występowały częściej w porównaniu do osób z jednym rozpoznaniem (p=0.0145; p=0.035).WnioskiZaburzenia seksualne występują częściej w grupie chorych z PD w porównaniu do pacjentów z rozpoznaniem schizofrenii. Brak posiadania partnera oraz czas leczenia psychiatrycznego powyżej 5 lat wiąże się z częstszym występowaniem zaburzeń seksualnych.