bluuebunny/crossref_metadata_2025 huggingface dataset:
PDGFRβ promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma
Authors: Garces de los Fayos Alonso I. , Zujo L. , Wiest I. , Kodajova P. , Timelthaler G. , Edtmayer S. , Zrimšek M. , Kollmann S. , Giordano C. , Kothmayer M. , Neubauer H. A. , Dey S. , Schlederer M. , Schmalzbauer B. S. , Limberger T. , Probst C. , Pusch O. , Högler S. , Tangermann S. , Merkel O. , Schiefer A. I. , Kornauth C. , Prutsch N. , Zimmerman M. , Abraham B. , Anagnostopoulos J. , Quintanilla-Martinez L. , Mathas S. , Wolf P. , Stoiber D. , Staber P. B. , Egger G. , Klapper W. , Woessmann W. , Look T. A. , Gunning P. , Turner S. D. , Moriggl R. , Lagger S. , Kenner L.
Published: August 2022

Background

Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive.

Methods and results

In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo.

Conclusions

We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.
Two-dimensional Ti3C2Tx MXene promotes electrophysiological maturation of neural circuits
Authors: Li Yige , Hu Yangnan , Wei Hao , Cao Wei , Qi Yanru , Zhou Shan , Zhang Panpan , Li Huawei , Li Geng-Lin , Chai Renjie
Published: August 2022

Background

The ideal neural interface or scaffold for stem cell therapy shall have good biocompatibility promoting survival, maturation and integration of neural stem cells (NSCs) in targeted brain regions. The unique electrical, hydrophilic and surface-modifiable properties of Ti3C2Tx MXene make it an attractive substrate, but little is known about how it interacts with NSCs during development and maturation.

Results

In this study, we cultured NSCs on Ti3C2Tx MXene and examined its effects on morphological and electrophysiological properties of NSC-derived neurons. With a combination of immunostaining and patch-clamp recording, we found that Ti3C2Tx MXene promotes NSCs differentiation and neurite growth, increases voltage-gated current of Ca2+ but not Na+ or K+ in matured neurons, boosts their spiking without changing their passive membrane properties, and enhances synaptic transmission between them.

Conclusions

These results expand our understanding of interaction between Ti3C2Tx MXene and NSCs and provide a critical line of evidence for using Ti3C2Tx MXene in neural interface or scaffold in stem cell therapy.
Metformin and histone deacetylase inhibitor based anti-inflammatory nanoplatform for epithelial-mesenchymal transition suppression and metastatic tumor treatment
Authors: Jiang Tianze , Xie Laozhi , Zhou Songlei , Liu Yipu , Huang Yukun , Mei Ni , Ma Fenfen , Gong Jingru , Gao Xiaoling , Chen Jun
Published: August 2022

Epithelial-mesenchymal transition (EMT), a differentiation process with aberrant changes of tumor cells, is identified as an initial and vital procedure for metastatic processes. Inflammation is a significant inducer of EMT and provides an indispensable target for blocking EMT, however, an anti-inflammatory therapeutic with highlighted safety and efficacy is deficient. Metformin is a promising anti-inflammatory agent with low side effects, but tumor monotherapy with an anti-inflammation drug could generate therapy resistance, cell adaptation or even promote tumor development. Combination therapies with various anti-inflammatory mechanisms can be favorable options improving therapeutic effects of metformin, here we develop a tumor targeting hybrid micelle based on metformin and a histone deacetylase inhibitor propofol-docosahexaenoic acid for efficient therapeutic efficacies of anti-inflammatory drugs. Triptolide is further encapsulated in hybrid micelles for orthotopic tumor therapies. The final multifunctional nanoplatforms (HAOPTs) with hyaluronic acid (HA) modification can target tumor efficiently, inhibit tumor cell EMT processes, repress metastasis establishment and suppress metastatic tumor development in a synergistic manner. Collectively, the results afford proof of concept that the tumor targeting anti-inflammatory nanoplatform can provide a potent, safe and clinical translational approach for EMT inhibition and metastatic tumor therapy.
Emerging trends in the nanomedicine applications of functionalized magnetic nanoparticles as novel therapies for acute and chronic diseases
Authors: Dash Sabyasachi , Das Tuhin , Patel Paritosh , Panda Pritam Kumar , Suar Mrutyunjay , Verma Suresh K.
Published: August 2022

High-quality point-of-care is critical for timely decision of disease diagnosis and healthcare management. In this regard, biosensors have revolutionized the field of rapid testing and screening, however, are confounded by several technical challenges including material cost, half-life, stability, site-specific targeting, analytes specificity, and detection sensitivity that affect the overall diagnostic potential and therapeutic profile. Despite their advances in point-of-care testing, very few classical biosensors have proven effective and commercially viable in situations of healthcare emergency including the recent COVID-19 pandemic. To overcome these challenges functionalized magnetic nanoparticles (MNPs) have emerged as key players in advancing the biomedical and healthcare sector with promising applications during the ongoing healthcare crises. This critical review focus on understanding recent developments in theranostic applications of functionalized magnetic nanoparticles (MNPs). Given the profound global economic and health burden, we discuss the therapeutic impact of functionalized MNPs in acute and chronic diseases like small RNA therapeutics, vascular diseases, neurological disorders, and cancer, as well as for COVID-19 testing. Lastly, we culminate with a futuristic perspective on the scope of this field and provide an insight into the emerging opportunities whose impact is anticipated to disrupt the healthcare industry.

Graphical Abstract
Tailor-made natural and synthetic grafts for precise urethral reconstruction
Authors: Tan Qinyuan , Le Hanxiang , Tang Chao , Zhang Ming , Yang Weijie , Hong Yazhao , Wang Xiaoqing
Published: August 2022

Injuries to the urethra can be caused by malformations, trauma, inflammation, or carcinoma, and reconstruction of the injured urethra is still a significant challenge in clinical urology. Implanting grafts for urethroplasty and end-to-end anastomosis are typical clinical interventions for urethral injury. However, complications and high recurrence rates remain unsatisfactory. To address this, urethral tissue engineering provides a promising modality for urethral repair. Additionally, developing tailor-made biomimetic natural and synthetic grafts is of great significance for urethral reconstruction. In this work, tailor-made biomimetic natural and synthetic grafts are divided into scaffold-free and scaffolded grafts according to their structures, and the influence of different graft structures on urethral reconstruction is discussed. In addition, future development and potential clinical application strategies of future urethral reconstruction grafts are predicted.
Hypertoxic self-assembled peptide with dual functions of glutathione depletion and biosynthesis inhibition for selective tumor ferroptosis and pyroptosis
Authors: Gao Yang , Li Yun , Cao Hongmei , Jia Haixue , Wang Dianyu , Ren Chunhua , Wang Zhongyan , Yang Cuihong , Liu Jianfeng
Published: August 2022

Abundant glutathione (GSH) is a biological characteristic of lots of tumor cells. A growing number of studies are utilizing GSH depletion as an effective adjuvant therapy for tumor. However, due to the compensatory effect of intracellular GSH biosynthesis, GSH is hard to be completely exhausted and the strategy of GSH depletion remains challenging. Herein, we report an l-buthionine-sulfoximine (BSO)-based hypertoxic self-assembled peptide derivative (NSBSO) with dual functions of GSH depletion and biosynthesis inhibition for selective tumor ferroptosis and pyroptosis. The NSBSO consists of a hydrophobic self-assembled peptide motif and a hydrophilic peptide derivative containing BSO that inhibits the synthesis of GSH. NSBSO was cleaved by GSH and thus experienced a morphological transformation from nanoparticles to nanofibers. NSBSO showed GSH-dependent cytotoxicity and depletion of intracellular GSH. In 4T1 cells with medium GSH level, it depleted intracellular GSH and inactivated GSH peroxidase 4 (GPX4) and thus induced efficient ferroptosis. While in B16 cells with high GSH level, it exhausted GSH and triggered indirect increase of intracellular ROS and activation of Caspase 3 and gasdermin E, resulting in severe pyroptosis. These findings demonstrate that GSH depletion- and biosynthesis inhibition-induced ferroptosis and pyroptosis strategy would provide insights in designing GSH-exhausted medicines.

Graphical Abstract
Engineering nano-drug biointerface to overcome biological barriers toward precision drug delivery
Authors: Waheed Saquib , Li Zhibin , Zhang Fangyingnan , Chiarini Anna , Armato Ubaldo , Wu Jun
Published: August 2022

The rapid advancement of nanomedicine and nanoparticle (NP) materials presents novel solutions potentially capable of revolutionizing health care by improving efficacy, bioavailability, drug targeting, and safety. NPs are intriguing when considering medical applications because of their essential and unique qualities, including a significantly higher surface to mass ratio, quantum properties, and the potential to adsorb and transport drugs and other compounds. However, NPs must overcome or navigate several biological barriers of the human body to successfully deliver drugs at precise locations. Engineering the drug carrier biointerface can help overcome the main biological barriers and optimize the drug delivery in a more personalized manner. This review discusses the significant heterogeneous biological delivery barriers and how biointerface engineering can promote drug carriers to prevail over hurdles and navigate in a more personalized manner, thus ushering in the era of Precision Medicine. We also summarize the nanomedicines' current advantages and disadvantages in drug administration, from natural/synthetic sources to clinical applications. Additionally, we explore the innovative NP designs used in both non-personalized and customized applications as well as how they can attain a precise therapeutic strategy.
Identification and ultrasensitive photoelectrochemical detection of LncNR_040117: a biomarker of recurrent miscarriage and antiphospholipid antibody syndrome in platelet-derived microparticles
Authors: Sun Zhiwei , Zhou Qian , Yang Yufei , Li Lei , Yu Mengru , Li Hui , Li Aihua , Wang Xietong , Jiang Yanyan
Published: August 2022

The abnormal expression of long non-coding RNAs (LncRNAs) in platelet-derived microparticles (PMPs) is closely related to immune disorders and may lead to antiphospholipid antibody syndrome and recurrent miscarriage. To understand the association between the LncRNAs in PMPs and RM/APS, the differences in the expression of LncRNAs in RM/APS patients and healthy controls were analyzed. Microarray analysis and RT-qPCR detection proved that RM/APS patient exhibited high levels of LncNR_040117 expression. The lentiviral silent expression transfection of HTR-8/SVneo cells indicated that LncNR_040117 downregulation decreased the activity of HTR-8/SVneo cells and inhibited the MAPK signaling pathway, further confirming the biomarker proficiency of LncNR_040117 for RM/APS. After that, we proposed a β-In2S3@g-C3N4nanoheterojunction-based photoelectrochemical (PEC) biosensor to achieve the ultrasensitive detection of LncNR_040117. The nanoheterojunction aids in the effective separation of photogenerated carriers and significantly improve the photocurrent response of the biosensor. The conjugation of LncNR_040117 onto the PEC biosensing platform increased the steric hindrance between electrolyte and electrode, subsequently decreasing the photocurrent signal. The PEC biosensor showed a wide detection range of 0.1–106fM and a low limit of detection of 0.025 fM. For clinical sample testing, the results of the PEC and RT-qPCR were highly consistent. Overall, LncNR_040117 in PMPs was identified as an effective biomarker for RM/APS and could be accurately detected by the proposed PEC biosensor, which is expected to provide a reliable diagnostic platform for RM/APS.
Hyperlipidemia does not influence clinical outcome in arthroscopic treatment of femoroacetabular impingement syndrome
Authors: Yang Fan , Huang Hong-Jie , Zhang Zhu , Zhang Xin , Wang Jian-Quan
Published: August 2022

Background

Cholesterol can trigger degenerative processes in the chondrocytes. The internal layer of the hip labral consists of cartilage-specific type II collagen-positive fibrocartilage. The purpose of this study was to compare outcomes after arthroscopy labral repair in FAIS patients with preoperative hyperlipidemia to a control group with no hyperlipidemia.

Methods

Data were prospectively collected and retrospectively reviewed for FAIS patients who had arthroscopy 2019. Patients with hyperlipidemia were 1:1 propensity-score matched to patients without hyperlipidemia. Patient-reported outcomes (HOS-ADL, iHOT-12, mHHS), VAS scores, radiographic measures, performed procedures, complications, and revision surgery were compared and analyzed for both groups.

Results

A total of 41 patients with hyperlipidemia and 41 patients without hyperlipidemia were found using propensity-score matching. When compared to preoperative levels, both groups demonstrated significant improvements in PROs and VAS scores at the final follow-up. Besides, there were no significant differences in preoperative scores and final outcome scores between the groups. Besides, there were no other differences in revision rate and the rate of meeting the PASS and MCID between the study and the control groups.

Conclusion

It was demonstrated in this study that FAIS patients with hyperlipidemia can expect to experience similar good short-term patient-reported outcomes as compared with patients without hyperlipidemia.

Level of evidence

Case-series study; Level of Evidence: Level III.
Genome-wide interrogation of structural variation reveals novel African-specific prostate cancer oncogenic drivers
Authors: Gong Tingting , Jaratlerdsiri Weerachai , Jiang Jue , Willet Cali , Chew Tracy , Patrick Sean M. , Lyons Ruth J. , Haynes Anne-Maree , Pasqualim Gabriela , Brum Ilma Simoni , Stricker Phillip D. , Mutambirwa Shingai B. A. , Sadsad Rosemarie , Papenfuss Anthony T. , Bornman Riana M. S. , Chan Eva K. F. , Hayes Vanessa M.
Published: August 2022

Background

African ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub-Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation.

Methods

Using whole genome sequencing and best practice workflows, we performed a comprehensive analysis of SVs for 180 (predominantly Gleason score ≥ 8) prostate tumours derived from 115 African, 61 European and four ancestrally admixed patients. We investigated the landscape and relationship of somatic SVs in driving ethnic disparity (AfricanversusEuropean), with a focus on African men from southern Africa.

Results

Duplication events showed the greatest ethnic disparity, with a 1.6- (relative frequency) to 2.5-fold (count) increase in African-derived tumours. Furthermore, we found duplication events to be associated withCDK12inactivation andMYCcopy number gain, and deletion events associated withSPOPmutation. Overall, African-derived tumours were 2-fold more likely to present with a hyper-SV subtype. In addition to hyper-duplication and deletion subtypes, we describe a new hyper-translocation subtype. While we confirm a lowerTMPRSS2-ERGfusion-positive rate in tumours from African cases (10%versus33%), novel African-specific PCa ETS family member andTMPRSS2fusion partners were identified, includingLINC01525, FBXO7,GTF3C2,NTNG1andYPEL5. Notably, we found 74 somatic SV hotspots impacting 18 new candidate driver genes, withCADM2,LSAMP,PTPRD,PDE4DandPACRGhaving therapeutic implications for African patients.

Conclusions

In this first African-inclusive SV study for high-risk PCa, we demonstrate the power of SV interrogation for the identification of novel subtypes, oncogenic drivers and therapeutic targets. Identifying a novel spectrum of SVs in tumours derived from African patients provides a mechanism that may contribute, at least in part, to the observed ethnic disparity in advanced PCa presentation in men of African ancestry.
Clinical trial design in the era of precision medicine
Authors: Fountzilas Elena , Tsimberidou Apostolia M. , Vo Henry Hiep , Kurzrock Razelle
Published: August 2022

Recent rapid biotechnological breakthroughs have led to the identification of complex and unique molecular features that drive malignancies. Precision medicine has exploited next-generation sequencing and matched targeted therapy/immunotherapy deployment to successfully transform the outlook for several fatal cancers. Tumor and liquid biopsy genomic profiling and transcriptomic, immunomic, and proteomic interrogation can now all be leveraged to optimize therapy. Multiple new trial designs, including basket and umbrella trials, master platform trials, and N-of-1 patient-centric studies, are beginning to supplant standard phase I, II, and III protocols, allowing for accelerated drug evaluation and approval and molecular-based individualized treatment. Furthermore, real-world data, as well as exploitation of digital apps and structured observational registries, and the utilization of machine learning and/or artificial intelligence, may further accelerate knowledge acquisition. Overall, clinical trials have evolved, shifting from tumor type-centered to gene-directed and histology-agnostic trials, with innovative adaptive designs and personalized combination treatment strategies tailored to individual biomarker profiles. Some, but not all, novel trials now demonstrate that matched therapy correlates with superior outcomes compared to non-matched therapy across tumor types and in specific cancers. To further improve the precision medicine paradigm, the strategy of matching drugs to patients based on molecular features should be implemented earlier in the disease course, and cancers should have comprehensive multi-omic (genomics, transcriptomics, proteomics, immunomic) tumor profiling. To overcome cancer complexity, moving from drug-centric to patient-centric individualized combination therapy is critical. This review focuses on the design, advantages, limitations, and challenges of a spectrum of clinical trial designs in the era of precision oncology.
Mucin O-glycan-microbiota axis orchestrates gut homeostasis in a diarrheal pig model
Authors: Xia Bing , Zhong Ruqing , Wu Weida , Luo Chengzeng , Meng Qingshi , Gao Qingtao , Zhao Yong , Chen Liang , Zhang Sheng , Zhao Xin , Zhang Hongfu
Published: August 2022

Background

Post-weaning diarrhea in piglets reduces growth performance and increases mortality, thereby causing serious economic losses. The intestinal epithelial cells and microbiota reciprocally regulate each other in order to maintain intestinal homeostasis and control inflammation. However, a relative paucity of research has been focused on the host-derived regulatory network that controls mucin O-glycans and thereby changes gut microbiota during diarrhea in infancy. At the development stage just after birth, the ontogeny of intestinal epithelium, immune system, and gut microbiota appear similar in piglets and human infants. Here, we investigated the changes of mucin O-glycans associated with gut microbiota using a diarrheal post-weaned piglet model.

Results

We found that diarrhea disrupted the colonic mucus layer and caused aberrant mucin O-glycans, including reduced acidic glycans and truncated glycans, leading to an impaired gut microenvironment. Subsequently, the onset of diarrhea, changes in microbiota and bacterial translocation, resulting in compromised epithelial barrier integrity, enhanced susceptibility to inflammation, and mild growth faltering. Furthermore, we found the activation of NLRP3 inflammasome complexes in the diarrheal piglets when compared to the healthy counterparts, triggered the release of proinflammatory cytokines IL-1β and IL-18, and diminished autophagosome formation, specifically the defective conversion of LC3A/B I into LC3A/B II and the accumulation of p62. Additionally, selective blocking of the autophagy pathway by 3-MA led to the reduction in goblet cell-specific gene transcript levels in vitro.

Conclusions

We observed that diarrheal piglets exhibited colonic microbiota dysbiosis and mucosal barrier dysfunction. Our data demonstrated that diarrhea resulted in the activation of inflammasomes and autophagy restriction along with aberrant mucin O-glycans including reduced acidic glycans and truncated glycans. The results suggested the mucin O-glycans-microbiota axis is likely associated with diarrheal pathogenesis. Our study provides novel insights into the pathophysiology of early-weaning-induced diarrheal disease in piglets and potentially understanding of disease mechanisms of diarrhea for human infants. Understanding the molecular pathology and pathogenesis of diarrhea is a prerequisite for the development of novel and effective therapies. Our data suggest that facilitating O-glycan elongation, modifying the microbiota, and developing specific inhibitors to some key inflammasomes could be the options for therapy of diarrhea including human infants.

Graphical abstract
α-Dystrobrevin knockout mice have increased motivation for appetitive reward and altered brain cannabinoid receptor 1 expression
Authors: Hawkes Cheryl A. , Heath Christopher J. , Sharp Matthew M. , Górecki Dariusz C. , Carare Roxana O.
Published: August 2022

α-Dystrobrevin (α-DB) is a major component of the dystrophin-associated protein complex (DAPC). Knockout (KO) of α-DB in the brain is associated with astrocytic abnormalities and loss of neuronal GABA receptor clustering. Mutations in DAPC proteins are associated with altered dopamine signaling and cognitive and psychiatric disorders, including schizophrenia. This study tested the hypothesis that motivation and associated underlying biological pathways are altered in the absence of α-DB expression. Male wildtype and α-DB KO mice were tested for measures of motivation, executive function and extinction in the rodent touchscreen apparatus. Subsequently, brain tissues were evaluated for mRNA and/or protein levels of dysbindin-1, dopamine transporter and receptor 1 and 2, mu opioid receptor 1 (mOR1) and cannabinoid receptor 1 (CB1). α-DB KO mice had significantly increased motivation for the appetitive reward, while measures of executive function and extinction were unaffected. No differences were observed between wildtype and KO animals on mRNA levels of dysbindin-1 or any of the dopamine markers. mRNA levels of mOR1were significantly decreased in the caudate-putamen and nucleus accumbens of α-DB KO compared to WT animals, but protein levels were unaltered. However, CB1 protein levels were significantly increased in the prefrontal cortex and decreased in the nucleus accumbens of α-DB KO mice. Triple-labelling immunohistochemistry confirmed that changes in CB1 were not specific to astrocytes. These results highlight a novel role for α-DB in the regulation of appetitive motivation that may have implications for other behaviours that involve the dopaminergic and endocannabinoid systems.
Isolated MLH1 Loss by Immunohistochemistry Because of Benign Germline MLH1 Polymorphisms
Authors: Bosch Dustin E. , Yeh Matthew M. , Salipante Stephen J. , Jacobson Angela , Cohen Stacey A. , Konnick Eric Q. , Paulson Vera A.
Published: August 2022

PURPOSE

Mismatch repair (MMR) immunohistochemistry (IHC) is frequently used to inform prognosis, select (immuno-)therapy, and identify patients for heritable cancer syndrome testing. However, false-negative and false-positive MMR IHC interpretations have been described.

MATERIALS AND METHODS

Following identification of discordant MMR IHC and DNA-based microsatellite instability testing in a patient with colorectal carcinoma, we retrospectively reviewed institutional archives to identify patient samples with similar discrepancies.

RESULTS

We report a patient with metastatic colorectal carcinoma who initially received immunotherapy on the basis of apparent isolated loss of MLH1 by IHC; notably, MLH1 promoter hypermethylation was negative. Subsequent evaluation of neoplastic tissue on a DNA-based targeted next-generation sequencing panel demonstrated microsatellite stability, low tumor mutational burden, and a benign MLH1 variant, MLH1 p.V384D, accompanied by loss of heterozygosity. The constellation of findings and repeat MLH1 IHC demonstrating retained expression using a different antibody-clone, supported reclassification of the neoplasm as MMR-proficient. Immunotherapy was discontinued, and cytotoxic chemotherapy was initiated. This index case of apparent discordance between MMR IHC and DNA-based microsatellite instability prompted a retrospective review of institutional archives to identify patient samples with similar discrepancies. Further evaluation of neoplasms harboring MLH1 p.V384D with loss of heterozygosity revealed systematic antibody-dependent interference. The review also identified a second IHC-interference candidate, MLH1 p.A441T.

CONCLUSION

This study confirms that rare germline polymorphisms can result in incorrect IHC results, potentially affecting selection of optimal therapy and the decision to pursue germline testing. This case further highlights the need for expert molecular pathologic review and communication between clinical and molecular oncology teams.
Immune Checkpoint Blockade Outcome in Small-Cell Lung Cancer and Its Relationship With Retinoblastoma Mutation Status and Function
Authors: Dowlati Afshin , Abbas Ata , Chan Timothy , Henick Brian , Wang Xuya , Doshi Parul , Fu Pingfu , Patel Jyoti , Kuo Fengshen , Chang Han , Balli David
Published: August 2022

PURPOSE

Immune checkpoint blockade (ICB) in conjunction with chemotherapy is approved for the treatment of extensive-stage small-cell lung cancer (SCLC). Although specific genomic abnormalities such as KEAP1 and STK11 gene mutations are associated with resistance to ICB in non-SCLC, no genomic abnormality has been found in association with resistance to ICB in SCLC.

MATERIALS AND METHODS

We first analyzed a retrospective cohort of 42 patients with SCLC treated with single-agent ICB or ICB combination (data set A). We then validated our results in a large prospective clinical trial of 460 patients (CheckMate 032, data set B). DNA and RNA sequencing were performed.

RESULTS

In data set A, patients treated with ICB with RB1 wild-type (WT) had a median overall survival (OS) of 23.1 months (95% CI, 9 to 37.5), whereas the RB1 mutant OS was 5 months (95% CI, 2.5 to 26; P = .04). Differentially expressed gene analysis between RB1 mutant and RB1 WT samples indicated the enrichment of downregulated immune-related genes and an immune exclusion phenotype among RB1 mutant but not in the RB1 WT tumor samples. We then assessed results from 460 patients enrolled in CheckMate 032, a trial of nivolumab (NIVO) or NIVO + ipilimumab only in SCLC. In this large cohort, RB1 WT patients had significantly improved outcome with NIVO therapy compared with mutant patients (hazard ratio, 1.41; 95% CI, 1.02 to 2.01; P = .041). High RB1 loss-of-function (LOF) signature scores significantly associated with neuroendocrine subtypes (ASCL1 and NeuroD1). However, neuroendocrine subtypes did not associate with OS. Remarkably, patients with lower RB1 LOF scores had longer OS following treatment with NIVO.

CONCLUSION

SCLC patients with RB1 WT status or lower RB1 LOF signature scores by transcriptomics have better outcomes with ICB monotherapy.
Cardiovascular Adjustments After Acute Heat Exposure
Authors: Romero Steven A. , Richey Rauchelle E. , Hemingway Holden W.
Published: August 2022

In this review, we highlight recent studies from our group and others that have characterized the cardiovascular adjustments that occur after acute heat exposure. Special emphasis will be placed on underlying mechanisms and clinical implications. Finally, we postulate that these acute cardiovascular adjustments may predict the long-term adaptive response to chronic heat therapy.
Pretest with Caution: Event-Study Estimates after Testing for Parallel Trends
Authors: Roth Jonathan
Published: August 2022

This paper discusses two important limitations of the common practice of testing for preexisting differences in trends (“ pre-trends”) when using difference-in-differences and related methods. First, conventional pre-trends tests may have low power. Second, conditioning the analysis on the result of a pretest can distort estimation and inference, potentially exacerbating the bias of point estimates and under-coverage of confidence intervals. I analyze these issues both in theory and in simulations calibrated to a survey of recent papers in leading economics journals, which suggest that these limitations are important in practice. I conclude with practical recommendations for mitigating these issues. (JEL A14, C23, C51)
Five Facts about the Distributional Income Effects of Monetary Policy Shocks
Authors: Amberg Niklas , Jansson Thomas , Klein Mathias , Picco Anna Rogantini
Published: August 2022

We document five facts about the distributional income effects of monetary policy shocks using Swedish administrative individual-level data. (i) The effects of monetary policy shocks are U shaped over the income distribution—that is, expansionary shocks increase the incomes of high- and low-income individuals relative to middle-income individuals. (ii) The large effects in the bottom are accounted for by the labor-income response and (iii) those in the top by the capital-income response. (iv) The heterogeneity in the labor-income response is due to the earnings heterogeneity channel, whereas (v) that in the capital-income response is due to the income composition channel. (JEL D31, E32, E52, J31)
Optimal Information Disclosure in Classic Auctions
Authors: Bergemann Dirk , Heumann Tibor , Morris Stephen , Sorokin Constantine , Winter Eyal
Published: August 2022

We characterize the revenue-maximizing information structure in the second-price auction. The seller faces a trade-off: more information improves the efficiency of the allocation but creates higher information rents for bidders. The information disclosure policy that maximizes the revenue of the seller is to fully reveal low values (where competition is high) but to pool high values (where competition is low). The size of the pool is determined by a critical quantile that is independent of the distribution of values and only dependent on the number of bidders. We discuss how this policy provides a rationale for conflation in digital advertising. (JEL D44, D82, D83, M37)
The Impact of Financial Assistance Programs on Health Care Utilization: Evidence from Kaiser Permanente
Authors: Adams Alyce , Kluender Raymond , Mahoney Neale , Wang Jinglin , Wong Francis , Yin Wesley
Published: August 2022

Most hospitals have financial assistance programs for low-income patients. We use administrative data from Kaiser Permanente to study the effects of financial assistance on health care utilization. Using a regression discontinuity design based on an income threshold for program eligibility, we find that financial assistance increases the likelihood of inpatient, ambulatory, and emergency department encounters by 3.6 pp (59 percent), 13.4 pp (20 percent), and 6.7 pp (53 percent), respectively, though effects dissipate three quarters after program receipt. Financial assistance also increases the detection and management of treatment-sensitive conditions (e.g., drugs treating diabetes), suggesting that financial assistance may increase receipt of high-value care. (JEL G51, I11, I12, I13, I32)
Clinical efficacy of motor imagery therapy based on fNIRs technology in rehabilitation of upper limb function after acute cerebral infarction
Authors: Dai Yi , Huang Fang , Zhu Yanfang
Published: August 2022

Objective: To investigate the efficacy of motor imagery therapy (MIT) based on functional near-infrared spectroscopy (fNIRs) technology in rehabilitation of upper limb function after cerebral infarction, so as to provide guidance for clinical practice.

Methods: A total of 84 patients with upper limb dysfunction after acute cerebral infarction admitted to Wuhan Puren Hospital from January 2020 to January 2021 were included in this study and randomly divided into two groups based on random number table method: experimental group and control group, with 42 cases in each group. Both groups were given active symptomatic treatment. The control group received conventional exercise rehabilitation, while the experimental group also received MIT based on fNIRs technology in addition to the treatment method adopted by the control group, lasting for eight weeks. The simplified Fugl-Meyer scale was utilized to evaluate the recovery of upper limb function, and the changes of Oxy-Hb and Deoxy-Hb concentrations in the frontal area of brain tissue were measured to evaluate the total effective rate of clinical rehabilitation.

Results: At four and eight weeks of treatment, the Fugl-Meyer scores of the two groups were significantly higher than those before treatment (P<0.05), and those in experimental group were significantly higher than those in control group (P<0.05), with no significant difference before treatment (P>0.05). After treatment, Oxy-Hb concentration in the experimental group was higher than that in the control group (P<0.05), while Deoxy-Hb concentration was lower than that in the control group, with a statistical significance (P<0.05). The total effective rate of rehabilitation in the experimental group was 88.10%, which was significantly higher than 73.81% in the control group (P<0.05).

Conclusion: Motor imagery therapy (MIT) Based on fNIRs technology has important clinical value in rehabilitation of upper limb function after cerebral infarction and is superior to conventional exercise rehabilitation alone, boasting a variety of effects, such as improving the curative effect, ameliorating blood oxygen in brain tissue, and promoting the rehabilitation of upper limb function of patients.

Randomized Controlled Trial: RCT Registration Number is ChiCTR1800015546.

doi: https://doi.org/10.12669/pjms.38.7.5344

How to cite this:Dai Y, Huang F, Zhu Y. Clinical efficacy of motor imagery therapy based on fNIRs technology in rehabilitation of upper limb function after acute cerebral infarction. Pak J Med Sci. 2022;38(7):1980-1985. doi: https://doi.org/10.12669/pjms.38.7.5344

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Projekt edukacyjny i wystawa Marian Rejewski – bydgoszczanin, matematyk, kryptolog, czyli jak promować bibliotekę, wykorzystując wizerunek patrona placówki
Authors: Pronobis-Sosnowska Ewa
Published: August 2022

THE EDUCATIONAL PROJECT AND EXHIBITION ENTITLED “MARIAN REJEWSKI, A BYDGOSZCZ NATIVE, MATHEMATICIAN AND CRYPTOLOGIST”; OR HOW TO PROMOTE A LIBRARY BY REFERENCE TO ITS NAMESAKE Poster exhibitions are one of the means of disseminating knowledge and information. Presentation board exhibitions using various external or internal display systems are developed by many institutions of culture, such as museums or libraries, for temporary or permanent display. The educational activity of the Marian Rejewski Regional Pedagogical Library in Bydgoszcz that involves exhibitions began in 2012, when the library was named after Marian Rejewski. One of the ways in which the library’s namesake was promoted and popularized in the community was through poster exhibitions. The article discusses these exhibitions, which were organized on the initiative of the library employees.
W bibliotece wciąż się dzieje… Współpraca instytucji oświatowych i kulturalnych w regionie na przykładzie Biblioteki Pedagogicznej w Sieradzu Filii w Wieruszowie
Authors: Żłobińska Elżbieta
Published: August 2022

THERE’S ALWAYS SOMETHING ON AT THE LIBRARY… CO-OPERATION BETWEEN REGIONAL EDUCATIONAL AND CULTURAL INSTITUTIONS: A CASE STUDY OF THE WIERUSZÓW BRANCH OF THE PEDAGOGICAL LIBRARY IN SIERADZ At a time of rapid development of digital culture, when younger and younger children use the internet, it is necessary to examine how the library functions in the local environment. The paper aims to present the activities of a small library in its local community. The fundamental question is whether these activities are only modelled on nationwide campaigns or involve the creativity of local librarians. The activities of the library are viewed and analysed from the perspective of two dichotomies: nationwide campaigns vs. local activities and regular vs. spontaneous events. It is vital for our consideration to view the library under discussion in the context of local educational and cultural institutions as well as the cooperation between them. This leads to a conclusion that the library branch has a positive impact on the local community and as such it may serve as a model of good practice for other libraries.
Informal Legacy and Exporting Among Sub-Saharan African Firms
Authors: Larsen Marcus M. , Witte Caroline T.
Published: August 2022

Around the world and especially in areas of widespread poverty, firms start their operations without registering with relevant authorities (i.e., in the informal economy). We explore whether firms that initiated their operations in the informal economy but later register have a higher propensity to export than firms that register at the time of their foundation. We reason that the experience of having operated informally provides formally registered firms with the advantage of low-cost and flexible exploration but also a domestic legitimacy liability. We suggest that these factors likely contribute to making foreign export markets more attractive after registration. Based on a comprehensive sample of sub-Saharan African firms, we find that, conditional on registration, firms with an informal legacy have a higher propensity to initiate exporting than firms that started their operations formally. We contribute with theoretical and policy-oriented insights on the dynamics of informality and exporting.

Funding: The work of M. M. Larsen was supported by the Carlsbergfondet [Grant CF17_0384].
BNCC COMO DISCURSO DE PADRONIZAÇÃO DE IDENTIDADES
Authors: Brandão Elielma Aparecida de Souza , Cruz Guibison Da Silva , Fernandes Luana Cristina Galdino
Published: August 2022

Este texto apresenta leituras e discussões realizadas no grupo de pesquisa Núcleo de Estudos em Currículo, Cultura e Subjetividades da Universidade Federal de Mato Grosso (UFMT). Problematizamos a Base Nacional Comum Curricular (BNCC) como produtora de padrões identitários. Tal visão prevê uma identidade fixa e apresenta uma única base para atender as demandas em vários contextos educacionais. Para Ernesto Laclau (2011), as identidades são múltiplas e se constituem em resposta à distintas demandas. Lopes (2015), defende uma política de currículo sem fundamentos. Assim, o objetivo deste trabalho centraliza-se em pensar a BNCC como uma política de currículo que se insere num campo de normatização e apresenta um discurso que tende a controlar identidades, sem levar em consideração as produções subjetivas contextuais. Ademais, busca-se problematizar seus fundamentos, salientando outras possibilidades de pensar esse documento. Para tal, utilizamo-nos de uma abordagem qualitativa de investigação, tendo como base a pesquisa bibliográfica, bem como a análise documental. Este texto fundamenta-se na Teoria do Discurso de Ernesto Laclau, que ajuda a problematizar questões normativas e identidades apresentadas como fixas. Nesse sentido, concluímos argumentando que a política de currículo se constitui através do antagonismo. Qualquer tentativa de consenso é sempre contingente, porque busca dominar o campo da discursividade em um terreno marcado pela tradução contínua. Assim, ponderamos que a BNCC tende a negar o caráter instável das identificações, das possibilidades de vir a pensar sujeito nos distintos contextos que produzem a política de currículo.
DISPUTA E CONFLITO PELA IMPLEMENTAÇÃO DE UMA EDUCAÇÃO DIFERENCIADA NA COMUNIDADE REMANESCENTE DE QUILOMBO DE SANTA RITA DO BRACUI
Authors: Correa Gabriel Siqueira , Da Silva Santos Carolina Silva
Published: August 2022

Este artigo tem como objetivo demonstrar a importância da educação como elemento instituinte de processos de territorialização/pertencimento de comunidades quilombolas. Para isso, utilizaremos como estudo de caso os processos de disputa em torno da educação quilombola implementada na Escola Municipal Aurea Pires, localizada no bairro do Bracuí, em Angra dos Reis. Destaca-se que essa proposta parte de dois distintos momentos de pesquisa: a primeira de uma inquietação provocada por visitas a escola como parte do trabalho de campo da disciplina de Estágio Supervisionado IV no curso de Geografia da Universidade do Estado do Rio de Janeiro em 2014, e posteriormente quando a mesma escola aparece como foco de tensão e disputa em tese que abordava os processos de resistência da comunidade quilombola de Santa Rita do Bracuí, realizada entre 2015-2018. Dessa forma, como metodologia foram feitos trabalhos de campo, entrevistas e cartografia participativa com os quilombolas durante o período de 2014-2019. Os resultados desse estudo demonstram que a escola é hoje um dos principais focos de estratégias de resistência da comunidade, à medida que a escola se tornou quilombola desde o censo de 2015, e está nos últimos anos buscando construir um projeto político pedagógico que atenda a comunidade.
VIRADA CURRICULAR NO MATO GROSSO E NA BAHIA: ALTERNATIVAS PEDAGÓGICAS COM OS KILOMBOS NOSSA SENHORA APARECIDA DO CHUMBO E DE BOITARACA
Authors: Rodrigues Fernandes Mille Caroline , Pereira Luciano Da Silva
Published: August 2022

Defendemos uma virada curricular a partir da perspectiva intercultural Kilombola que tem como centralidade a história oral sendo essa uma camada expressiva de uma  tecnologia de repactuação social  inadiável justamente pela perspectiva monocultural de currículo ainda em vigor. Partimos da ideia de que parece não se tratar mais de uma opção para os grupos marginalizados, mas sim de viabilizarmos reconexões visando o equilíbrio social, indo além do campo simbólico. Exploramos aspectos etnográficos nas imersões que realizamos em dois Kilombos contemporâneos estando esses em Mato Grosso e na Bahia. Trabalhamos com a noção de pesquisa engajada pela gravidade e riscos eminentes já enfrentados tanto nos espaços da educação básica quanto na educação escolar kilombola.
ANÁLISE DECOLONIAL DA SÉRIE “SIEMPRE BRUJA”: TRADUÇÃO INTERSEMIÓTICA OU ADAPTAÇÃO INTERCULTURAL?
Authors: Antunes Viviane Conceição , Dutra Thiago Renan Figueira
Published: August 2022

Atualmente, o processo de transformação de uma obra em outra, com características próprias, desperta, em grande medida, inquietações, em especial, no que concerne às obras levadas às plataformas digitais. Nesse contexto, o presente artigo tem como objetivo debruçar-se sobre os aspectos envolvidos no movimento de transposição do romance “Yo, bruja” (CHACÓN, 2015) ao streaming, por meio da série intitulada “Siempre bruja” (NETFLIX, 2019), identificando as especificidades do processo de tradução, aqui tratado como uma interpretação, baseada na negociação de sentidos (ECO, 2007). Ultrapassa, portanto, o aspecto intertextual, fazendo-nos refletir sobre o movimento de adaptação que, por sua vez, se caracteriza como um processo que considera os fatores extra-fílmicos envolvidos na transformação de uma obra literária em outra audiovisual (PAVIS, 2008). O questionamento que nos move é: “Siempre bruja” (NETFLIX, 2019) é o resultado de uma tradução intersemiótica (JAKOBSON, 1969; DINIZ, 1994; PLAZA, 2008) ou uma adaptação intercultural (PAVIS, 2008)? Visamos, portanto, respondê-lo sob o viés da decolonialidade (WALSH, 2012; 2013) e, para tal, será necessário, a partir de uma abordagem qualitativa de análise: i) verificar as principais características de ambas as obras, levantando aspectos para aprofundamento de uma análise crítica; ii) analisar a série “Siempre bruja” (NETFLIX, 2019), buscando compreender se se trata de um processo de tradução intersemiótica ou de adaptação intercultural; iii) ler criticamente a série sob o viés decolonial, examinando as diferenças e as proximidades entre as obras, posicionando-a metodologicamente; e iv) dar relevo à importância da adaptação intercultural crítica, conceito acunhado nesta pesquisa.
Avascular femoral head necrosis in young gymnasts: a pursuit of aetiology and management
Authors: Blümel Stefan , Leunig Michael , Manner Hannes , Tannast Moritz , Stetzelberger Vera M. , Ganz Reinhold
Published: August 2022

Aims

Avascular femoral head necrosis in the context of gymnastics is a rare but serious complication, appearing similar to Perthes’ disease but occurring later during adolescence. Based on 3D CT animations, we propose repetitive impact between the main supplying vessels on the posterolateral femoral neck and the posterior acetabular wall in hyperextension and external rotation as a possible cause of direct vascular damage, and subsequent femoral head necrosis in three adolescent female gymnasts we are reporting on.

Methods

Outcome of hip-preserving head reduction osteotomy combined with periacetabular osteotomy was good in one and moderate in the other up to three years after surgery; based on the pronounced hip destruction, the third received initially a total hip arthroplasty.

Results

The described pathology is quite devastating, and extensive joint preserving surgery (which has been shown successful in Perthes’ cases) was less successful in this patient cohort.

Conclusion

Supraselective angiography may be helpful to improve pathomechanical understanding and surgical decision making. Cite this article: Bone Jt Open 2022;3(9):666–673.