bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-World Treatment Patterns Among Patients With Metastatic Castration-Resistant Prostate Cancer: Results From an International Study
Authors: Barata Pedro C , Leith Andrea , Ribbands Amanda , Montgomery Rachel , Last Matthew , Arondekar Bhakti , Ivanova Jasmina , Niyazov Alexander 
Published: April 2023

Abstract

Background
There is limited real-world evidence on how increasing use of treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC) has influenced treatment decisions in metastatic castration-resistant prostate cancer (mCRPC). The study objective was to evaluate the impact of novel hormonal therapy (NHT) and docetaxel use in mCSPC on first-line treatment patterns among patients with mCRPC in 5 European countries and the United States (US).

Methods
Physician-reported data on patients with mCRPC from the Adelphi Prostate Cancer Disease Specific Program were descriptively analyzed.

Results
A total of 215 physicians provided data on 722 patients with mCRPC. Across 5 European countries and the US, 65% and 75% of patients, respectively, received NHT, and 28% and 9% of patients, respectively, received taxane chemotherapy as first-line mCRPC treatment. In Europe, patients who had received NHT in mCSPC (n = 76) mostly received taxane chemotherapy in mCRPC (55%). Patients who had received taxane chemotherapy, or who did not receive taxane chemotherapy or NHT in mCSPC (n = 98 and 434, respectively) mostly received NHT in mCRPC (62% and 73%, respectively). In the US, patients who had received NHT, taxane chemotherapy, or neither in mCSPC (n = 32, 12, and 72, respectively) mostly received NHT in mCRPC (53%, 83%, and 83%, respectively). Two patients in Europe were rechallenged with the same NHT.

Conclusions
These findings suggest that physicians consider mCSPC treatment history when making first-line treatment decisions in mCRPC. Further studies are needed to better understand optimal treatment sequencing, especially as new treatments emerge.
Risk of severe infections after the introduction of biologic DMARDs in people with newly diagnosed rheumatoid arthritis: a population-based interrupted time-series analysis
Authors: Zhou Vivienne Y , Lacaille Diane , Lu Na , Kopec Jacek A , Qian Yi , Nosyk Bohdan , Aviña-Zubieta J Antonio , Esdaile John M , Xie Hui 
Published: April 2023

Abstract

Objectives
To determine the impact of the introduction of biologic DMARDs (bDMARDs) on severe infections among people newly diagnosed with RA compared with non-RA individuals.

Methods
In this population-based retrospective cohort study using administrative data (from 1990–2015) for British Columbia, Canada, all incident RA patients diagnosed between 1995 and 2007 were identified. General population controls with no inflammatory arthritis were matched to RA patients based on age and gender, and were assigned the diagnosis date (i.e. index date) of the RA patients they were matched with. RA/controls were then divided into quarterly cohorts according to their index dates. The outcome of interest was all severe infections necessitating hospitalization or occurring during hospitalization after the index date. We calculated 8-year severe infection rates for each cohort and conducted interrupted time-series analyses to compare severe infection trends in RA/controls with index date during pre-bDMARDs (1995–2001) and post-bDMARDs (2003–2007) periods.

Results
A total of 60 226 and 588 499 incident RA/controls were identified. We identified 14 245 severe infections in RA, and 79 819 severe infections in controls. The 8-year severe infection rates decreased among RA/controls with increasing calendar year of index date in the pre-bDMARDs period, but increased over time only among RA, not controls, with index date in the post-bDMARDs period. The adjusted difference between the pre- and post-bDMARDs secular trends in 8-year severe infection rates was 1.85 (P = 0.001) in RA and 0.12 (P = 0.29) in non-RA.

Conclusion
RA onset after bDMARDs introduction was associated with an elevated severe infection risk in RA patients compared with matched non-RA individuals.
Emerging evidence for poxvirus‐mediated unfolded protein response: Lumpy skin disease virus maintains self‐replication by activating PERK and IRE1 signaling
Authors: Tan Jinlong , Liu Yinju , Yang Fan , Chen Guohua , Fang Yongxiang , He Xiaobing , Lou Zhongzi , Jia Huaijie , Jing Zhizhong , Li Weike 
Published: April 2023

AbstractThe monkeypox epidemic has attracted global attention to poxviruses. The cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a member of the poxvirus family, causes ER stress in vivo and in vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the significance of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK‐eIF2α and IRE1‐XBP1 signaling cascades rather than ATF6, implying that global translation and reduced XBP1 cleavage are deleterious to LSDV replication. Taken together, these findings indicate that LSDV is involved in the repression of global translational signaling, ER chaperone transcription, and ATF6 cleavage from the Golgi into the nucleus, thereby maintaining cell homeostasis; moreover, PERK and IRE1 activation contribute to LSDV replication. Our findings suggest that targeting UPR elements may be applied in response to infection from LSDV or even other poxviruses, such as monkeypox.
Surgical Correction of Posttraumatic Varus Deformity of the Distal Tibia Due to Medial Growth Arrest in Children and Adolescents: Surgical Technique
Authors: Schwartz Robert , Kotlarsky Pavel , Eidelman Mark 
Published: April 2023

Background:
Varus deformity of the distal tibia secondary to epiphyseal fracture and partial growth arrest is relatively common. Growth arrest of the medial part of the epiphysis leads to varus deformity of the distal tibia and fibular overgrowth. If the deformity is left untreated, the malalignment may lead to irreversible damage and early ankle joint osteoarthritis in the long term.
Several surgical techniques have been described in the literature to achieve correction and prevent late complications. These include the closure of the remaining epiphysis and various osteotomies around the ankle, using internal and external fixation.

Materials and Methods:
We report a technique that includes medial open wedge supramalleolar osteotomy, insertion of a structural cortical allograft and fixation with an anatomically contoured locking plate, completion of closure of the distal tibial physis, and distal fibular epiphysiodesis to prevent tibiofibular relations distortion. Part of this protocol is osteotomy of the distal fibula to prevent excessive pressure on the talus, and at the end of the operation, fibular fixation should be performed as well. In children with open physis and potential for significant leg length discrepancy, we recommend closure of the contralateral physis of the distal tibia and fibula. To the best of our knowledge, precise details of this protocol have not been described.

Conclusion:
We believe that this protocol is a reliable, accurate, and relatively simple method that provides not only anatomic correction and restoration of the ankle joint to prevent early ankle and subtalar arthritis but also addresses late complications, such as ipsilateral fibular overgrowth and limb length discrepancy.
Eosinophilic gastroenteritis: Pathogenesis, diagnosis, and treatment
Authors: Li Kaiwen , Ruan Gechong , Liu Shuang , Xu Tianming , Guan Kai , Li Ji , Li Jingnan 
Published: April 2023

Abstract
Eosinophilic gastroenteritis (EGE) is a gastrointestinal disorder of unclear etiology that is characterized by eosinophilic infiltration of the stomach and small intestine, and consists of mucosal, muscular, and serosal subtypes. Eosinophilic infiltration of the gastrointestinal tract is a fundamental histopathological characteristic of EGE and is driven by several T-helper type 2 (Th2)-dependent cytokines and induced by food allergy. Due to the lack of a diagnostic gold standard, EGE has a high rate of delayed diagnosis or misdiagnosis. However, several new diagnostic strategies have been developed, such as novel genetic biomarkers and imaging tests. Although dietary therapy and corticosteroids remain the common choices for EGE treatment, recent decades have seen the emergence of novel treatment alternatives, such as biologics that target particular molecules involved in the pathogenic process. Preliminary investigations and clinical trials have demonstrated the efficacy of biologics and provided additional insights for the era of refractory or corticosteroid-dependent EGE biologics.
Hydatid cyst of the psoas: case report and review of literature
Authors: Mhand Mohammed , Ramdani Abdelbassir , Khomssi Nabil , Rhoul Chafik , Bouhout Tariq , Serji Badr , El Harroudi Tijani 
Published: April 2023

Introduction:
Hydatid disease (HD) is a parasitic pathology that remains endemic in Morocco and poses a public health problem. Its location in the psoas muscle is a rare entity. We report this case highlighting the diagnostic challenges, therapeutic modalities as well as prognosis.

Case Presentation:
We report the case of a 40-year-old male patient without a notable pathological history, referred to our department for management of a paravertebral hydatid cyst mass with fluid density and scalloping on the verteral body on thoraco-abdomino-pelvic computed tomography scan. After a pretherapeutic assessment, the patient underwent an exploratory laparotomy which objective a deep right laterovertebral mass. The patient underwent a resection of the protruding dome, lavage using hydrogen peroxide and drainage of the residual cavity. The patient recovered well and was discharged 5 days later on albendazole 10 mg/kg/d. The anatomopathological analysis of the specimen confirmed the diagnosis of hydatid cyst. The evolution was satisfactory for the patient with a recall of 6 months.

Discussion:
Hydatidosis is an anthropozonosis caused by the larval form of Echinococcus granulosus. It can reach the psoas muscle by great circulation. The diagnosis of HD in the psoas is often difficult. Biology and imaging confirm the diagnosis and the standard treatment remains surgery.

Conclusion:
HD of the psoas is a rare entity. The diagnosis is based on biology and imaging, and radical treatment is surgery.
Antimicrobial resistance patterns in paediatric infections at Damascus Hospital, Syria: a retrospective cohort study
Authors: Kahal Fares , Helwani Ahmed , Torbey André , Alsaadi Aya , Mohsen Fatema , Al Bani Maher 
Published: April 2023

Background:
Antimicrobial resistance is the third top-ranking global causative of death. Ninety per cent of babies with sepsis who were admitted to the ICU in the Middle East had antibiotic-resistant bacteria. We aim to describe the epidemiology, culture findings, bacterial antibiotic resistance, as well as the outcomes of children who present with nosocomial or community-acquired infections.

Methods:
A retrospective observational cohort study was conducted to analyze children with positive culture results presenting with nosocomial or community-acquired infections in Damascus Hospital, Damascus, Syria, which is considered one of the biggest hospitals in Syria.

Results:
In all, 116 patients with 177 positive culture results were included in the study. However, 54 (47%) were males, and 62 (53%) were females. Ages ranged between 3 h and 13 years. Cases of positive culture results peaked at the age or period of 0–11 months, that is 59(50%). The most prevalent bacteria were Staphylococcus aureus (33%), Enterobacter (21%), Pseudomonas aeruginosa (15%) and Escherichia coli (12%). The most used antibiotics were ceftriaxone (70%), vancomycin (60%) and amikacin (25%). The highest bacterial antibiotic resistance occurred with third-generation cephalosporins, and the most antibiotic-resistant bacterium was P. aeruginosa. Nosocomial infections occurred in 51% of the patients. Death was the outcome of 16% of the patients.

Conclusion:
The situation regarding bacterial resistance to antibiotics is critical, with the most notable examples of these resisted antibiotics being ceftriaxone, cefepime, cefotaxime, trimethoprim, gentamycin, levofloxacin and piperacillin with tazobactam, and there is no doubt that this is a major contributing factor to the high prevalence of nosocomial infections and death rates found in this study.
Adjuvants influence the maturation of VRC01-like antibodies during immunization
Authors: Knudsen Maria L. , Agrawal Parul , MacCamy Anna , Parks K. Rachael , Gray Matthew D. , Takushi Brittany N. , Khechaduri Arineh , Coler Rhea N. , LaBranche Celia C. , Montefiori David , Stamatatos Leonidas 
Published: April 2023

ABSTRACTOnce naïve B cells expressing germline VRC01-class B cell receptors become activated by germline-targeting immunogens, they enter germinal centers and undergo affinity maturation. Booster immunizations with heterologous Envs are required for the full maturation of VRC01-class antibodies. Here, we examined whether and how three adjuvants, Poly(I:C), GLA-LSQ, or Rehydragel, that activate different pathways of the innate immune system, influence the rate and type of somatic mutations accumulated by VRC01-class BCRs that become activated by the germline-targeting 426c.Mod.Core immunogen and the heterologous HxB2.WT.Core booster immunogen. We report that although the adjuvant used had no influence on the durability of plasma antibody responses after the prime, it influenced the plasma VRC01 antibody titers after the boost and the accumulation of somatic mutations on the elicited VRC01 antibodies.ONE SENTENCE SUMMARYVRC01-class BCRs with different somatic mutations are being selected depending on the adjuvant used during immunization
Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes
Authors: Yu Katharine , Basu Amrita , Yau Christina , Wolf Denise M , Goodarzi Hani , Bandyopadhyay Sourav , Korkola James E , Hirst Gillian L , Asare Smita ,   I-SPY 2 TRIAL investigators, Demichele Angela , Hylton Nola , Yee Douglas , Esserman Laura , van ’t Veer Laura , Sirota Marina 
Published: April 2023

AbstractDrug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes. In this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival. We found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2-receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel-resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line.
ALDH2 dysfunction accelerates ESCC pathogenesis
Authors: Flashner Samuel , Shimonosono Masataka , Matsuura Norihiro , Ohashi Shinya , Klein-Szanto Andres J. , Diehl J. Alan , Chen Che-Hong , Mochly-Rosen Daria , Nakagawa Hiroshi 
Published: April 2023

ABSTRACTThe alcohol metabolite acetaldehyde is a potent human carcinogen. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulates and causes genotoxic stress in cells expressing the dysfunctional ALDH2E487Kmutant protein linked toALDH2*2, the single nucleotide polymorphism highly prevalent amongst East Asians. Chronic alcohol users with heterozygousALDH2*2display an increased risk for the development of esophageal squamous cell carcinoma (ESCC) and other alcohol-related cancers. However, how ALDH2 influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three dimensional organoids, and xenograft models. We find that alcohol exposure results in increased organoid formation and tumor growth concurrent with increased reactive oxygen species (ROS), increased DNA damage, and the enrichment of putative cancer stem cells (CSCs) characterized by high CD44 expression. Pharmacological activation of ALDH2 function by Alda-1 inhibits this phenotype, indicating that acetaldehyde is the primary driver of these changes. ALDH2 dysfunction also affects response to a commonly used chemotherapy for the treatment of ESCC. We find that Aldh2 dysfunction facilitated enrichment of CSCs following cisplatin-induced cell death and oxidative stress in murine organoids. Together, these data provide evidence that alcohol exposure, results in more aggressive tumors through enrichment of CSCs, which is augmented by ALDH2 dysfunction.
Melanoma clonal subline analysis uncovers heterogeneity-driven immunotherapy resistance mechanisms
Authors: Gruen Charli , Yang Howard H. , Sassano Antonella , Wu Emily , Gopalan Vishaka , Marie Kerrie L. , Castro Andrea , Mehrabadi Farid Rashidi , Wu Chih Hao , Church Isabella , Needle Gabriel A. , Smith Cari , Chin Sung , Ebersole Jessica , Marcelus Christina , Fon Anyen , Liu Huaitian , Malikic Salem , Sahinalp Cenk , Carter Hanna , Hannenhalli Sridhar , Day Chi-Ping , Lee Maxwell P. , Merlino Glenn , Pérez-Guijarro Eva 
Published: April 2023

ABSTRACTIntratumoral heterogeneity (ITH) can promote cancer progression and treatment failure, but the complexity of the regulatory programs and contextual factors involved complicates its study. To understand the specific contribution of ITH to immune checkpoint blockade (ICB) response, we generated single cell-derived clonal sublines from an ICB-sensitive and genetically and phenotypically heterogeneous mouse melanoma model, M4. Genomic and single cell transcriptomic analyses uncovered the diversity of the sublines and evidenced their plasticity. Moreover, a wide range of tumor growth kinetics were observedin vivo, in part associated with mutational profiles and dependent on T cell-response. Further inquiry into melanoma differentiation states and tumor microenvironment (TME) subtypes of untreated tumors from the clonal sublines demonstrated correlations between highly inflamed and differentiated phenotypes with the response to anti-CTLA-4 treatment. Our results demonstrate that M4 sublines generate intratumoral heterogeneity at both levels of intrinsic differentiation status and extrinsic TME profiles, thereby impacting tumor evolution during therapeutic treatment. These clonal sublines proved to be a valuable resource to study the complex determinants of response to ICB, and specifically the role of melanoma plasticity in immune evasion mechanisms.
Genetic variation in promoter region of the bovine LAP3 gene associated with estimated breeding values of milk production traits and clinical mastitis in dairy cattle
Authors: Worku Destaw , Gowane Gopal , Verma Archana 
Published: April 2023

AbstractThe purpose of this study was to identify genetic variants in the promoter and 5’UTR regions of bovine leucine amino peptidase three (LAP3) gene and analysed their associations with estimated breeding values (EBVs) of milk production traits and clinical mastitis in Sahiwal and Karan Fries cattle. Eleven SNPs were identified within the region under study of the LAP3 gene, including seven promoter variants (rs717156555: C>G, rs720373055: T>C, rs715189731: A>G, rs516876447: A>G, rs4618572 69: C>T, rs136548163: C>T, and rs720349928: G>A) and four 5’UTR variants (rs717884982: C>T, rs722359733: C>T, rs481631804: C>T and rs462932574: T>G). Out of them, 10 SNPs variants were found in both Sahiwal and Karan Fries cattle, with one SNP variant (rs481631804: C>T) being unique to Karan Fries cattle. Seven of these identified SNPs were chosen for association analyses. Individual SNP based association analysis revealed that two SNPs (rs720373055: T>C and rs7203499 28: G>A) were significantly associated with EBVs of lactation milk yield (LMY), 305-day milk yield (305dMY), and one significant association of SNP rs722359733: C>T with lactation length (LL) was observed. Haplotype based association analysis indicated that diplotypes are significantly associated with EBVs of LMY, 305dMY, and LL, individuals with H1H3 (CTACGCT/GCGTACG) being linked to higher lactation performance than other diplotypes. Further logistic regression analysis revealed that, animals with diplotype H1H3 was less susceptible to the incidence of clinical mastitis than other cows, as the odds ratio for the non-incidence of clinical mastitis was found to be low. Altogether, variations in the LAP3 gene promoter could be used as a genetic marker, most notably diplotype H1H3, may greatly benefit the simultaneous improvement of mastitis resistance and milk yield traits in dairy cattle. Moreover, bioinformatics analysis predicted that the SNPs rs720373055: T>C, rs715189731:A>G and rs720349928: G>A is located in the core promoter region and in TFBs, play key role in regulation of studied phenotypes.