Miracle-dz/UniFAR-FTUs huggingface dataset:
Case Report: Re-Sensitization to Gefitinib in Lung Adenocarcinoma Harboring EGFR Mutation and High PD-L1 Expression After Immunotherapy Resistance, Which Finally Transform Into Small Cell Carcinoma

The treatment sequence of immunotherapy (IO) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is of great importance for the survival of non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. Here, we reported an advanced lung adenocarcinoma case concurrent with EGFR sensitive mutation and high PD-L1 expression (>50%) that was administrated with gefitinib firstly, and then became resistant to EGFR-TKI. He received the strategy of immunity-combined chemo-radiotherapy and responded significantly. However, the disease re-progressed after 10 months. Surprisingly, the tumor re-sensitized to gefitinib for 13 months. At final, following the treatment pressure of TKI-IO combination therapy-TKI strategy, tumor clone eventually transformed into small cell lung carcinoma (SCLC). For one thing, our study provided novel approach and extended the treatment spectra of overcoming immunotherapy resistance after EGFR resistance in driver oncogene-mutated NSCLC. For another thing, our case is the first time to report that SCLC transformation can be achieved after gefitinib–pembrolizumab–gefitinib resistance in EGFR sensitive mutation NSCLC, providing a new condition for SCLC transformation.
Language Can Obscure as Well as Facilitate Apparent-Theory of Mind Performance: Part 2—The Case of Dyslexia in Adulthood

Many studies imply causal links between linguistic competencies and Theory of Mind (ToM). But despite Dyslexia being a prime example of linguistic deficits, studies on whether it is related to ToM have been relatively unforthcoming. In the first of 2 studies (N = 89), independently-diagnosed dyslexic adults and non-dyslexic adults were presented with false-belief vignettes via computer, answering 4 types of question (Factual, Inference, 1st-order ToM & 2nd-order ToM). Dyslexia related to lower false-belief scores. Study 2 (N = 93) replicated this result with a non-computer-based variant on the false-belief task. We considered the possibility that the apparent-issue with ToM is caused by processing demands more associated to domains of cognition such as language, than to ToM itself. Addressing this possibility, study 2 additionally utilised the ToM30Q questionnaire, designed largely to circumvent issues related to language and memory. Principal-Components analysis extracted 4 factors, 2 capturing perceptual/representational ToM, and the other 2 capturing affective components related to ToM. The ToM30Q was validated via its associations to a published measure of empathy, replication of the female gender advantage over males, and for one factor from the ToM30Q there was a correlation with an existing published index of ToM. However, when we considered the performance of dyslexic and non-dyslexic participants using the ToM30Q, we found absolutely no difference between them. The contrasting findings from our 2 studies here, arguably offer the first experimental evidence with adults, that there is in fact no ToM deficit in dyslexia. Additionally, this finding raises the possibility that some other groups considered in some sense atypical, failed ToM tasks, not because they actually have a ToM deficit at all, but rather because they are asked to reveal their ToM competence through cognitive domains, such as language and memory.
Immunoreactivity of Sera From Low to Moderate Malaria-Endemic Areas Against Plasmodium vivax rPvs48/45 Proteins Produced in Escherichia coli and Chinese Hamster Ovary Systems

P48/45 is a conserved gametocyte antigen involved in Plasmodium parasite fertilization. A recombinant Plasmodium vivax P48/45 (Pvs48/45) protein expressed in Escherichia coli (E. coli) was highly antigenic and immunogenic in experimental animals and elicited specific transmission-blocking (TB) antibodies in a previous pilot study. Here, a similar Pvs48/45 gene was expressed in Chinese Hamster Ovary (CHO) cells and we compared its immunoreactivity with the E. coli product. Specific antibody titers were determined using plasma from Colombian individuals (n=227) living in endemic areas where both P. vivax and P. falciparum are prevalent and from Guatemala (n=54) where P. vivax is highly prevalent. In Colombia, plasma seroprevalence to CHO-rPvs48/45 protein was 46.3%, while for E. coli-rPvs48/45 protein was 36.1% (p<0.001). In Guatemala, the sero prevalence was 24.1% and 14.8% (p<0.001), respectively. Reactivity index (RI) against both proteins showed an age-dependent increase. IgG2 was the predominant subclass and the antibody avidity index evaluated by ELISA ranged between 4-6 mol/L. Ex vivo P. vivax mosquito direct membrane feeding assays (DMFA) performed in presence of study plasmas, displayed significant parasite transmission-blocking (TB), however, there was no direct correlation between antibody titers and oocysts transmission reduction activity (%TRA). Nevertheless, DMFA with CHO rPvs48/45 affinity purified IgG showed a dose response; 90.2% TRA at 100 μg/mL and 71.8% inhibition at 10 μg/mL. In conclusion, the CHO-rPvs48/45 protein was more immunoreactive in most of the malaria endemic places studied, and CHO-rPvs48/45 specific IgG showed functional activity, supporting further testing of the protein vaccine potential.
Guaianolide Sesquiterpenes With Significant Antiproliferative Activities From the Leaves of Artemisia argyi

Four new guaiane-type sesquiterpenes, argyin H–K (1–4), and two known analogues (5 and 6) were isolated from the leaves of Artemisia argyi Lévl et Vant. The new compounds were characterized by the basic analysis of the spectroscopic data obtained (1H NMR, 13C NMR, HMBC, and NOESY experiments), and their absolute configurations were determined by empirical approaches, combined with the exciton chirality method and electronic circular dichroism calculations. To further understand the antitumor effects of A. argyi, the antiproliferative activities of these compounds against A549, MCF-7, and HepG2 cell lines were tested in vitro using CCK-8 assays. The results showed that these compounds had significant antiproliferative effects on MCF-7, with IC50 values of 15.13–18.63 μM, which were superior to that of oxaliplatin (i.e., IC50 22.20 μM).
Plasmodium vivax Gametocytes Adherence to Bone Marrow Endothelial Cells

In a Plasmodium vivax infection, it was shown a proportionally increased on gametocyte distribution within the bone marrow aspirant, suggesting a role of this organ as a reservoir for this parasite stage. Here, we evaluated the ex vivo cytoadhesive capacity of P. vivax gametocytes to bone marrow endothelial cells (HBMEC) and investigated the involvement of some receptors in the cytoadhesion process by using transfected CHO cells (CHO-ICAM1, CHO-CD36 and CHO-VCAM), wild type (CHO-K1) or deficient in heparan and chondroitin sulfate (CHO-745). Ex-vivo cytoadhesion assays were performed using a total of 44 P. vivax isolates enriched in gametocyte stages by Percoll gradient in the different cell lines. The majority of isolates (88.9%) were able to adhere to HBMEC monolayer. ICAM1 seemed to be the sole receptor significantly involved. CD-36 was the receptor with higher adhesion rate, despite no significance was noticed when compared to CHO-745. We demonstrated that gametocyte P. vivax adheres ex vivo to bone marrow endothelial cells. Moreover, P. vivax gametocytes display the ability to adhere to all CHO cells investigated, especially to CHO-ICAM1. These findings bring insights to the comprehension of the role of the bone marrow as a P. vivax reservoir and the potential impact on parasite transmission to the vector.
Association Between Air Pollution and Acute Coronary Syndromes During Lockdown for COVID-19: Results From the Terni Hub Center

Background: During the lockdown for COVID-19, a massive decrease in hospital admissions for acute coronary syndrome (ACS) and a drop in air pollution were both detected in Italy. Our aim was to investigate the possible association between these two events at the Province of Terni, one of the most polluted urban and industrial area in Central Italy. Methods: We analyzed data of daily 24-h urban air concentrations of particulate matter (PM)10 and PM2.5 from fixed station monitoring network located in the main city centers of the Terni province, and accesses for ACS at the catheterization laboratory of the Cardiological Hub Center of the Terni University Hospital during lockdown. A comparison was made with data corresponding to the same lockdown time period of years 2019, 2018, and 2017. Results: Invasive procedures for ACS decreased in 2020 (n = 49) as compared with previous years (n = 93 in 2019, n = 109 in 2018, and n = 89 in 2017, p < 0.001). Conversely, reductions in average PM10 (20.7 μg/m3) and PM2.5 (14.7 μg/m3) in 2020 were consistent with a long-term decreasing trend, being comparable to those recorded in 2019 and 2018 (all p > 0.05) and slightly lower than 2017 (p < 0.05). The Granger-causality test demonstrated the lack of association between time-varying changes in air pollution and the number of procedures for ACS. Conclusions: Our results did not support the hypothesis that reduction in invasive procedures for ACS during lockdown was linked to an air cleaning effect. Reasons other than reduced air pollution should be sought to explain the observed decrease in ACS procedures.
Prospective Observational Study of Bisphosphonate-Related Osteonecrosis of the Jaw in Multiple Myeloma: Microbiota Profiling and Cytokine Expression

Purpose Define incidence and risk factors of osteonecrosis of the jaw (ONJ) and explore oral microbial signatures and host immune response as reflected by cytokine changes in saliva and serum in multiple myeloma (MM) patients on bisphosphate (BP) therapy. Patients and Methods A single center observational prospective study of MM patients (n = 110) on >2 years of BP, none had ONJ at enrollment. Patients were followed every 3 months for 18 months with clinical/dental examination and serial measurements of inflammatory cytokines, bone turnover markers, and angiogenic growth factors. Oral microbiota was characterized by sequencing of 16S rRNA gene from saliva. Results Over the study period 14 patients (13%) developed BRONJ, at a median of 5.7 years (95% CI: 1.9–12.0) from MM diagnosis. Chronic periodontal disease was the main clinically observed risk factor. Oral microbial profiling revealed lower bacterial richness/diversity in BRONJ. Streptococcus intermedius, S. mutans, and S. perioris were abundant in controls; S. sonstellatus and S anginosus were prevalent in BRONJ. In the saliva, at baseline patients who developed BRONJ had higher levels of MIP-1β; TNF-α and IL-6 compared to those without BRONJ, cytokine profile consistent with M-1 macrophage activation. In the serum, patients with BRONJ have significantly lower levels of TGF beta and VEGF over the study period. Conclusion Periodontal disease associated with low microbial diversity and predominance of invasive species with a proinflammatory cytokine profile leading to tissue damage and alteration of immunity seems to be the main culprit in pathogenesis of BRONJ.
Local Drivers of Change in Southern Ocean Ecosystems: Human Activities and Policy Implications

Local drivers are human activities or processes that occur in specific locations, and cause physical or ecological change at the local or regional scale. Here, we consider marine and land-derived pollution, non-indigenous species, tourism and other human visits, exploitation of marine resources, recovery of marine mammals, and coastal change as a result of ice loss, in terms of their historic and current extent, and their interactions with the Southern Ocean environment. We summarise projected increases or decreases in the influence of local drivers, and projected changes to their geographic range, concluding that the influence of non-indigenous species, fishing, and the recovery of marine mammals are predicted to increase in the future across the Southern Ocean. Local drivers can be managed regionally, and we identify existing governance frameworks as part of the Antarctic Treaty System and other instruments which may be employed to mitigate or limit their impacts on Southern Ocean ecosystems.
Superb Microvascular Imaging Technology Can Improve the Diagnostic Efficiency of the BI-RADS System

Background To explore whether superb microvascular imaging (SMI)SMI can improve the diagnostic efficiency by evaluating the vascular index (VI) and vascular architecture (VA) in breast lesions. Methods This is a retrospective study of data collected prospectively for research use. Taking 225 consecutive cases of breast lesions from November 2016 to December 2017 as a training set, the VI values and VA types of benign and malignant lesions were calculated based on the pathological results. Taking 238 consecutive cases of breast lesions from January 2018 to October 2018 as the verification set, the diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated to compare the diagnostic efficacy. Results The training set included 225 breast lesions and the validation set 238 breast lesions. The VI value in the malignant group (10.3 ± 8.0) was significantly higher than that in the benign group (4.3 ± 5.0)(P<0.001). A VI value of 4.05 was used as the diagnostic threshold for differentiating benign from malignant lesions, with a sensitivity of 80.5%, a specificity of 61.9%, an accuracy of 71.1%, a PPV of 62.9%, a NPV of 76.9%, and an area under the curve of 0.758 (0.696-0.819). There was a significant difference in the types of benign and malignant VA (P < 0.001), and the PPV of the root hair-like and crab claw-like VAs were 93.9% and 100.0%, respectively. The diagnostic sensitivity, specificity, accuracy, PPV, NPV and area under the AUC curve were 58.0%, 98.2%, 97.0%, 70.3% and 0.781, respectively (95%CI: 0.719-0.844). SMI combined with conventional ultrasound improved the diagnostic specificity (70.0% vs. 90.0%), accuracy (87.4% vs. 96.6%), and PPV (82.5% vs. 93.2%) without decreasing the diagnostic sensitivity (99.3%), yielded higher diagnostic performance with the area under the ROC curve was 0.941 (95%CI: 0904-0.979) compared with conventional US alone (P < 0.001). Conclusion A VI value 4.05 is a cut-off value with good diagnostic efficacy. The residual root-like and crab claw-like VAs are the characteristic VAs of malignant lesions. Conventional ultrasound combined with the VI and VA can improve the diagnostic specificity, accuracy and PPV without reducing the diagnostic sensitivity.
Behavioral Framework of Immersive Technologies (BehaveFIT): How and Why Virtual Reality can Support Behavioral Change Processes

The design and evaluation of assisting technologies to support behavior change processes have become an essential topic within the field of human-computer interaction research in general and the field of immersive intervention technologies in particular. The mechanisms and success of behavior change techniques and interventions are broadly investigated in the field of psychology. However, it is not always easy to adapt these psychological findings to the context of immersive technologies. The lack of theoretical foundation also leads to a lack of explanation as to why and how immersive interventions support behavior change processes. The Behavioral Framework for immersive Technologies (BehaveFIT) addresses this lack by 1) presenting an intelligible categorization and condensation of psychological barriers and immersive features, by 2) suggesting a mapping that shows why and how immersive technologies can help to overcome barriers and finally by 3) proposing a generic prediction path that enables a structured, theory-based approach to the development and evaluation of immersive interventions. These three steps explain how BehaveFIT can be used, and include guiding questions for each step. Further, two use cases illustrate the usage of BehaveFIT. Thus, the present paper contributes to guidance for immersive intervention design and evaluation, showing that immersive interventions support behavior change processes and explain and predict 'why' and 'how' immersive interventions can bridge the intention-behavior-gap.
Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes

Acute Myeloid Leukaemia (AML) is a commonly occurring severe haematological malignancy, with most patients exhibiting sub-optimal clinical outcomes. Therapy resistance significantly contributes towards failure of traditional and targeted treatments, disease relapse and mortality in AML patients. The mechanisms driving therapy resistance in AML are not fully understood, and approaches to overcome therapy resistance are important for curative therapies. To date, most studies have focused on therapy resistant mechanisms inherent to leukaemic cells (e.g., TP53 mutations), overlooking to some extent, acquired mechanisms of resistance through extrinsic processes. In the bone marrow microenvironment (BMME), leukaemic cells interact with the surrounding bone resident cells, driving acquired therapy resistance in AML. Growing evidence suggests that macrophages, highly plastic immune cells present in the BMME, play a role in the pathophysiology of AML. Leukaemia-supporting macrophage subsets (CD163+CD206+) are elevated in preclinical in vivo models of AML and AML patients. However, the relationship between macrophages and therapy resistance in AML warrants further investigation. In this review, we correlate the potential links between macrophages, the development of therapy resistance, and patient outcomes in AML. We specifically focus on macrophage reprogramming by AML cells, macrophage-driven activation of anti-cell death pathways in AML cells, and the association between macrophage phenotypes and clinical outcomes in AML, including their potential prognostic value. Lastly, we discuss therapeutic targeting of macrophages, as a strategy to circumvent therapy resistance in AML, and discuss how emerging genomic and proteomic-based approaches can be utilised to address existing challenges in this research field.
In Vivo Safety of Tumor Treating Fields (TTFields) Applied to the Torso

Background Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional, anti-mitotic treatment modality that targets rapidly dividing cancerous cells, utilizing low intensity, alternating electric fields at cancer-cell-type specific frequencies. TTFields therapy is approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM) in the US, Europe, Israel, Japan, and China. The favorable safety profile of TTFields in patients with GBM is partially attributed to the low rate of mitotic events in normal, quiescent brain cells. However, specific safety evaluations are warranted at locations with known high rates of cellular proliferation, such as the torso, which is a primary site of several of the most aggressive malignant tumors. Methods The safety of delivering TTFields to the torso of healthy rats at 150 or 200 kHz, which were previously identified as optimal frequencies for treating multiple torso cancers, was investigated. Throughout 2 weeks of TTFields application, animals underwent daily clinical examinations, and at treatment cessation blood samples and internal organs were examined. Computer simulations were performed to verify that the targeted internal organs of the torso were receiving TTFields at therapeutic intensities (≥ 1 V/cm root mean square, RMS). Results No treatment-related mortality was observed. Furthermore, no significant differences were observed between the TTFields-treated and control animals for all examined safety parameters: activity level, food and water intake, stools, motor neurological status, respiration, weight, complete blood count, blood biochemistry, and pathological findings of internal organs. TTFields intensities of 1 to 2.5 V/cm RMS were confirmed for internal organs within the target region. Conclusions This research demonstrates the safety of therapeutic level TTFields at frequencies of 150 and 200 kHz when applied as monotherapy to the torso of healthy rats.
Loss of Knee Flexion and Femoral Rollback of the Medial-Pivot and Posterior-Stabilized Total Knee Arthroplasty During Early-Stance of Walking in Chinese Patients

Background The medial-pivot (MP) prosthesis was developed to produce more physiological postoperative knee kinematics and better patient satisfaction than traditional prostheses, but outcomes are inconsistent in different studies of Caucasian patients. This study aimed to investigate the postoperative patient satisfaction and in vivo knee kinematics of the MP and posterior-stabilized (PS) prosthesis during gait activity in Chinese patients. Methods A retrospective analysis of 12 patients was received for this study in each MP group and PS group. Patient-reported satisfaction level and Forgotten Joint Score (FJS) were evaluated with questionnaires. A dual fluoroscopic imaging system was used to investigate in vivo knee kinematics of MP and PS total knee arthroplasty (TKA) during treadmill walking at a speed of 0.4 m/s. Results Comparable promising patient satisfaction and overall FJS (MP 60.7 ± 15.35 vs. PS 51.3 ± 17.62, p = 0.174) were found between the MP and PS groups. Peak flexion appeared at around 70% of gait cycle with values of 52.4 ± 7.4° for MP and 50.1 ± 3.6° for PS groups (no difference). Both groups maintained a stable position at the stance phase and began to translated anteriorly at toe-off with an amount of 4.5 ± 2.3 mm in the MP and 6.6 ± 2.7 mm in the PS (p = 0.08) group until late swing. The range of this external rotation motion was 5.9 ± 4.8 and 6.2 ± 4.1° (p = 0.79) for the MP and PS, respectively. Conclusion A similar knee kinematics pattern characterized by a loss of early-stance knee flexion and femoral rollback during walking was observed in the MP and PS TKAs. Our study confirmed similar effectiveness of MP TKA compared to PS TKA in Chinese patients, while the change of knee kinematics of both implants during slow walking should be noted.
Acute Kidney Injury Induced Lupus Exacerbation Through the Enhanced Neutrophil Extracellular Traps (and Apoptosis) in Fcgr2b Deficient Lupus Mice With Renal Ischemia Reperfusion Injury

Renal ischemia is the most common cause of acute kidney injury (AKI) that might be exacerbate lupus activity through neutrophil extracellular traps (NETs) and apoptosis. Here, the renal ischemia reperfusion injury (I/R) was performed in Fc gamma receptor 2b deficient (Fcgr2b-/-) lupus mice and the in vitro experiments. At 24 h post-renal I/R injury, NETs in peripheral blood neutrophils and in kidneys were detected using myeloperoxidase (MPO), neutrophil elastase (NE) and citrullinated histone H3 (CitH3), as well as kidney apoptosis (activating caspase-3), which were prominent in Fcgr2b-/- mice more compared to wild-type (WT). After 120 h renal-I/R injury, renal NETs (using MPO and NE) were non-detectable, whereas glomerular immunoglobulin (Ig) deposition and serum anti-dsDNA were increased in Fcgr2b-/- mice. These results imply that renal NETs at 24 h post-renal I/R exacerbated the lupus nephritis at 120 h post-renal I/R injury in Fcgr2b-/- lupus mice. Furthermore, a Syk inhibitor attenuated NETs, that activated by phorbol myristate acetate (PMA; a NETs activator) or lipopolysaccharide (LPS; a potent inflammatory stimulator), more prominently in Fcgr2b-/- neutrophils than the WT cells as determined by dsDNA, PAD4 and MPO. In addition, the inhibitors against Syk and PAD4 attenuated lupus characteristics (serum creatinine, proteinuria, and anti-dsDNA) in Fcgr2b-/- mice at 120 h post-renal I/R injury. In conclusion, renal I/R in Fcgr2b-/- mice induced lupus exacerbation at 120 h post-I/R injury partly because Syk-enhanced renal NETs led to apoptosis-induced anti-dsDNA, which was attenuated by a Syk inhibitor.