Miracle-dz/UniFAR-FTUs huggingface dataset:
Real-World Data of Pyrotinib-Based Therapy in Metastatic HER2-Positive Breast Cancer: Promising Efficacy in Lapatinib-Treated Patients and in Brain Metastasis

Purpose Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. This study reported the first real-world data of pyrotinib-based therapy in metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on efficacy in lapatinib-treated patients and in brain metastasis. Materials and Methods One hundred thirteen patients with metastatic HER2-positive BC treated with pyrotinib-based therapy in Fudan University Shanghai Cancer Center under non-clinical trial settings from September 1, 2018 to March 1, 2019 were included. Results Over half patients have received more than two lines of systematic therapy and exposed to two or more kinds of anti-HER2 agents. Most patients received a combined therapy, commonly of pyrotinib plus capecitabine, or vinorelbine or trastuzumab. Median progression-free survival (PFS) was 6.3 months (range, 5.54 to 7.06 months) and objective response rate (ORR) was 29.5%, with two patients (1.9%) achieving complete response. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (9.0 months vs. 5.4 months, p=0.001). ORR for lapatinib-treated patients was 23.2%. Thirty-one of 113 patients have brain metastasis. Median PFS was 6.7 months and intracranial ORR was 28%. For patients without concurrent radiotherapy and/or brain surgery, the ORR was very low (6.3%). But for patients receiving concurrent radiotherapy and/or brain surgery, the ORR was 66.7%, and three patients achieved complete response. Most common adverse event was diarrhea. Conclusion Pyrotinib-based therapy demonstrated promising effects in metastatic HER2-positive BC and showed activity in lapatinib-treated patients. For patients with brain metastasis, pyrotinib-based regimen without radiotherapy showed limited efficacy, but when combined with radiotherapy it showed promising intracranial control.
Antagonistic interaction between male‐killing and cytoplasmic incompatibility induced by Cardinium and Wolbachia in the whitefly, Bemisia tabaci

Cardinium and Wolbachia are maternally inherited bacterial symbionts of arthropods that can manipulate host reproduction by increasing the fitness of infected females. Here, we report that Cardinium and Wolbachia coinfection induced male‐killing and cytoplasmic incompatibility (CI) when they coexisted in a cryptic species of whitefly, Bemisia tabaci Asia II7. Cardinium and Wolbachia symbionts were either singly or simultaneously localized in the bacteriocytes placed in the abdomen of B. tabaci nymphs and adults. Cardinium–Wolbachia coinfection induced male‐killing and resulted in a higher female sex ratio in the intraspecific amphigenetic progeny of Asia II7 ICWH and ICWL lines; interestingly, male‐killing induction was enhanced with increased Cardinium titer. Moreover, single infection of Wolbachia induced partial CI in the Asia II7 IW line and resulted in reduced fecundity, higher embryonic mortality, and lower female sex ratio. The uninfected Asia II7 IU line had significantly higher fecundity, lower embryonic and nymphal mortalities, and a lower level of CI than both the Wolbachia‐infected Asia II7 IW line and the Cardinium–Wolbachia‐coinfected Asia II7 ICWH line. Our findings indicate that Cardinium–Wolbachia coinfection induced male‐killing, which may have had antagonistic effects on Wolbachia‐induced CI in the Asia II7 whiteflies. For the first time, our study revealed that B. tabaci Asia II7 reproduction is co‐manipulated by Cardinium and Wolbachia endosymbionts.
Structural insights of catalytic mechanism in mutant pyrazinamidase of Mycobacterium tuberculosis

Abstract Pyrazinamidase (PZase) is a member of Fe-dependent amidohydrolases that activates pyrazinamide (PZA) into active pyrazinoic acid (POA). PZA, a nicotinamide analogue, is an essential first-line drug used in Mycobacterium tuberculosis (Mtb) treatment. The active form of PZA, POA, is toxic and potently inhibits the growth of latent Mtb, which makes it possible to shorten the conventional 9-month tuberculosis treatment to 6 months. In this study, an extensive molecular dynamics simulation was carried out to the study the resistance mechanism offered by the three mutations Q10P and D12A and G97D. Our results showed that two regions Gln10-His43, Phe50-Gly75 are profoundly affected by these mutations. Among the three mutations, Q10P and D12A mutations strongly disturb the communication among the catalytic triad (Asp8, Lys98 and Cys138). The oxyanion hole is formed between the backbone nitrogen atoms of A134 and C138 which stabilizes the hydroxyl anion of nicotinamide. The D12A mutation greatly disturbs the oxyanion hole formation followed by the Q10P and G97D. Our results also showed that these mutations destabilize the interaction between Fe2+ ion and Asp49, His51, His57 and His71. The binding pocket analysis showed that these mutations increase the cavity volume, which results in loose binding of PZA. MMGBSA analyzes have shown that these mutations reduce the binding affinity to the PZA drug. Our results may provide useful information for the design of new and effective PZase inhibitors based on structural information of WT and mutant PZases. Communicated by Ramaswamy H. Sarma
Awareness and experiences of cosmetic treatment providers with body dysmorphic disorder in Saudi Arabia

Body Dysmorphic Disorder (BDD) is defined as a constant obsession with one’s external appearance and flaws, and it falls under the criteria of neuropsychiatric disorders. Individuals suffering from this disorder may seek unnecessary cosmetic procedures from cosmetic treatment providers such as dermatologists or plastic surgeons. Cosmetic treatments have become readily available, which has led to an influx of undiagnosed BDD patients electing to undergo such treatments. Therefore, physicians should have the clinical knowledge about BDD to diagnose and manage these cases to avoid psychological and physical harm to these patients. However, there were no studies conducted in our region to assess the awareness of BDD among physicians who provide cosmetic treatments with regards to their attitude toward such cases and how they would manage it. This study aims to assess the awareness of Body Dysmorphic Disorder among Saudi physicians who provide cosmetic treatments. We conducted an observational cross-sectional study among physicians practicing in hospitals and cosmetic clinics in Riyadh and Jeddah city (Saudi Arabia), who perform cosmetic procedures, namely dermatologists, plastic surgeons, and otorhinolaryngologists. A paper-based questionnaire consisting of multiple-choice questions was distributed among them. The total number of participants was 155 physicians: 113 (72.9%) males and 42 (27.1%) females. Eighty-two (52.9%) participants reported that they have been familiar with the diagnostic criteria of BDD for a long time and ninety-nine (63.8%) reported being familiar with the clinical picture of BDD. Sixty-three (40.6%) participants estimated the prevalence of BDD cases seen in cosmetic practice to range from 1%-5%, and most agreed on an equal prevalence of BDD among female and male patients. Half of the participants (n = 76) (49%) reported that they sometimes share knowledge about BDD with patients whom they suspect to suffer from this condition. In conclusion, cosmetic treatment providers in Saudi Arabia are aware of BDD, but we have identified a discrepancy between the self-reported participant knowledge of diagnostic criteria and their ability to accurately estimate the prevalence of BDD cases seen in clinical practice.
Phases of match-play in professional Australian Football: Distribution of physical and technical performance

ABSTRACT The current study aimed to describe the distribution of physical and technical performance during the different phases of play in professional Australian Football. The phases of play (offence, defence, contested play, umpire stoppages, set shots and goal resets) were manually coded from video footage for a single team competing in 18 matches in the Australian Football League. Measures of physical performance including total distance (m), average speed (m · min−1), low-speed running (LSR, <14.4 km h−1), high-speed running (HSR, >14.4 km h−1), accelerations (2.78 m · s−2) and decelerations (−2.78 m · s−2) were derived from each phase of play via global positioning system (GPS) devices. Technical skill data including tackles, handballs and kicks were obtained from a commercial statistics provider and derived from each phase of play. Linear mixed-effects models and effect sizes were used to assess and reflect the differences in physical and technical performance between the six phases of play. Activity and recovery cycles, defined as periods where the ball was in or out of play were also described using mean and 95% confidence intervals. The analysis showed that several similarities existed between offence and defence for physical performance metrics. Contested play involved the highest total distance, LSR, accelerations, decelerations and tackles compared to all other phases. Offence and defence involved the highest average speed and HSR running distances. Handballs and kicks were highest during offence, while tackles were highest during contested play, followed by defence. Activity and recovery cycles involved mean durations of ~110 and ~39 s and average speeds of ~160 and ~84 m · min−1, respectively. The integration of video, GPS and technical skill data can be used to investigate specific phases of Australian Football match-play and subsequently guide match analysis and training design.
Hurricane effects on Neotropical lizards span geographic and phylogenetic scales

Significance Extreme climate events can act as agents of natural selection. We demonstrate that lizards hit by Hurricanes Irma and Maria in 2017 passed on their large, strong-gripping toepads to the next generation of lizards. Moreover, we found that across 12 insular populations of Anolis sagrei, and 188 Anolis species across the Neotropics, those hit by more hurricanes in the last 70 y tended to have proportionately larger toepads. Our study suggests that hurricanes can have long-term and large-scale evolutionary impacts that transcend biogeographic and phylogenetic scales. As hurricanes become more severe due to climate change, these extreme climate events may have a much larger impact on the evolutionary trajectory of the affected ecological communities than previously appreciated. Extreme climate events such as droughts, cold snaps, and hurricanes can be powerful agents of natural selection, producing acute selective pressures very different from the everyday pressures acting on organisms. However, it remains unknown whether these infrequent but severe disruptions are quickly erased by quotidian selective forces, or whether they have the potential to durably shape biodiversity patterns across regions and clades. Here, we show that hurricanes have enduring evolutionary impacts on the morphology of anoles, a diverse Neotropical lizard clade. We first demonstrate a transgenerational effect of extreme selection on toepad area for two populations struck by hurricanes in 2017. Given this short-term effect of hurricanes, we then asked whether populations and species that more frequently experienced hurricanes have larger toepads. Using 70 y of historical hurricane data, we demonstrate that, indeed, toepad area positively correlates with hurricane activity for both 12 island populations of Anolis sagrei and 188 Anolis species throughout the Neotropics. Extreme climate events are intensifying due to climate change and may represent overlooked drivers of biogeographic and large-scale biodiversity patterns.
Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma

Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c. 1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis.
The roles of GRP81 as a metabolic sensor and inflammatory mediator

GPR81 (also named as HCA1) is a member of a subfamily of orphan G‐protein coupled receptors (GPCRs), coupled to Gi‐type G proteins. GPR81 was discovered in 2001 and identified as the only known endogenous receptor of lactate under physiological conditions in 2008, which opened a new field of research on how lactate may act as a signal molecule along with the GPR81 expression in the roles of metabolic process and inflammatory response. Recent studies showed that the physiological functions of GPR81 include lipid metabolism in adipose tissues, metabolic excitability in the brain, cellular development, and inflammatory response modulation. These findings may reveal a novel therapeutic strategy to treat clinical, metabolic, and inflammatory diseases. This article will summarize past research on GPR81, including its characteristics of distribution and expression, functional residues, pharmacological, and physiological agonists, involvement in signal transduction, and pharmacological applications.
Effect of a 12-Week Almond-Enriched Diet on Biomarkers of Cognitive Performance, Mood, and Cardiometabolic Health in Older Overweight Adults

Long term nut consumption is associated with reduced risk of coronary heart disease and better cognitive function. This study examined supplementing habitual diets with almonds or carbohydrate-rich snack foods (providing 15% energy) on biomarkers of cardiovascular and metabolic health, mood and cognitive performance. Participants (overweight/obese, 50–80 years) were randomised to an almond-enriched diet (AED) or isocaloric nut-free diet (NFD) for 12 weeks. Body weight, blood lipids, glucose, insulin, blood pressure (BP), arterial stiffness, cell adhesions molecules, C reactive protein (CRP), mood, and cognitive performance (working memory primary outcome), dietary profiles and energy intake/expenditure were measured at baseline and Week 12 in 128 participants (n = 63 AED, n = 65 NFD). Compared with NFD, AED was associated with altered macro and micronutrient profiles, but no differences in energy intake or expenditure. The AED significantly reduced triglycerides and SBP but there were no other changes in cardiometabolic biomarkers, mood, or cognitive performance. The inclusion of almonds in the diet improves aspects of cardiometabolic health without affecting cognitive performance or mood in overweight/obese adults.
A quantitative framework for modeling COVID-19 risk during adjuvant therapy using published randomized trials of glioblastoma in the elderly

Abstract Background During the ongoing COVID-19 pandemic, contact with the health care system for cancer treatment can increase risk of infection and associated mortality. Treatment recommendations must consider this risk for elderly and vulnerable cancer patients. We reanalyzed trials in elderly glioblastoma (GBM) patients, incorporating COVID-19 risk, in order to provide a quantitative framework for comparing different radiation (RT) fractionation schedules on patient outcomes. Methods We extracted individual patient-level data for 1321 patients from Kaplan–Meier curves from 5 randomized trials on treatment of elderly GBM patients including available subanalyses based on O6-methylguanine-DNA methyltransferase (MGMT) methylation status. We simulated trial data with incorporation of COVID-19–associated mortality risk in several scenarios (low, medium, and high infection and mortality risks). Median overall survival and hazard ratios were calculated for each simulation replicate. Results Our simulations reveal how COVID-19–associated risks affect survival under different treatment regimens. Hypofractionated RT with concurrent and adjuvant temozolomide (TMZ) demonstrated the best outcomes in low and medium risk scenarios. In frail elderly patients, shorter courses of RT are preferable. In patients with methylated MGMT receiving single modality treatment, TMZ-alone treatment approaches may be an option in settings with high COVID-19–associated risk. Conclusions Incorporation of COVID-19–associated risk models into analysis of randomized trials can help guide clinical decisions during this pandemic. In elderly GBM patients, our results support prioritization of hypofractionated RT and highlight the utility of MGMT methylation status in decision making in pandemic scenarios. Our quantitative framework can serve as a model for assessing COVID-19 risk associated with treatment across neuro-oncology. Key Points • Re-analysis of randomized controlled trials in COVID-19 era gives insight on optimal treatment of GBM. • Hypofractionated RT or temozolomide alone may be reasonable options in high risk pandemic settings. • A quantitative framework incorporating COVID-19 risks can be applied across neuro-oncology.
Backward Running: Acute Effects on Sprint Performance in Preadolescent Boys

The aim of this study was to examine the acute effect of backward running (BwR) during warm-up on a 20-m sprint of boys’ performance, compared to forward running (FwR). Fourteen recreationally active preadolescent boys (aged 12.5 ± 0.5 years) were examined in 3 protocols: warm-up (control condition), warm-up with 3 × 10 m additional BwR sprints and warm-up with 3 × 10 m additional FwR sprints. Participants were evaluated 4 minutes after each protocol on a 20-m sprint and intermediate distances, as well as the rate of perceived exertion (RPE). Sprint speed across 10-20 m was significantly higher for the BwR warm-up compared to the regular warm-up (p < 0.05) and a significantly higher RPE after the BwR and FwR protocols compared to the control condition was recorded (p < 0.05). No significant difference was detected across the distances 0–5, 5–10, 0–10 and 0–20 m. Although adding 3 × 10-m sprints of BwR or FwR after the warm-up did not enhance performance in a 20 m sprint of preadolescent boys, the positive effect of BwR across 10–20 m distance suggests that BwR could be an alternative means for enhancing performance for certain phases of a sprint for this age. However, preadolescent boys’ response to different sprint conditioning exercise stimuli and the optimization of rest time to maximize performance remain to be determined.
INVESTIGATING KEY POST-PKS ENZYMES FROM GILVOCARCIN BIOSYNTHETIC PATHWAY

OF DISSERTATION INVESTIGATING KEY POST-PKS ENZYMES FROM GILVOCARCIN BIOSYNTHETIC PATHWAY Gilvocarcin V (GV) belongs to the angucycline class of antibiotics that possesses remarkable anticancer and antibacterial activities with low toxicity. Gilvocarcin exhibits its light induced anticancer activity by mediating crosslinking between DNA and histone H3. When photo-activated by near-UV light, the C8 vinyl group forms a [2+2] cycloadduct with thymine residues of double stranded DNA. D-fucofuranose is considered essential for histone H3 interactions. However, the poor water solubility has rendered it difficult to develop gilvocarcin as a drug. We aim to design novel gilvocarcin analogues with improved pharmaceutical properties through chemo-enzymatic synthesis and mutasynthesis. Previous studies have characterized many biosynthetic genes encoding the gilvocarcin biosynthetic skeleton. Despite these previous findings the exact functions of many other key genes are yet to be fully understood. Prior gene inactivation and cross-feeding experiments have revealed that the first isolable tetracyclic aromatic product undergoes a series of steps involving C–C bond cleavage followed by two Omethylations, a penultimate C-glycosylation and final lactone formation in order to fully develop the gilvocarcin structure. To provide a deeper understanding of these complex biochemical transformations, three specific aims were devised: 1) synthesis of the proposed intermediate and in vitro enzyme reactions revealed GilMT and GilM’s roles in gilvocaric biosynthesis; 2) utilizing in vitro studies the enzyme responsible for the C–C bond cleavage and its substrate were determined; 3) a small series of structural analogues of the intermediate from the gilvocarcin pathway was generated via chemical synthesis and fed to the mixture of the enzymes, GilMT and GilM. These reaction mixtures were then analyzed to establish the diversity of substrates tolerated by the enzymes.
Aqueous Inflammation and Ischemia-Related Biomarkers in Neovascular Glaucoma with Stable Iris Neovascularization

ABSTRACT Purpose: To characterize the aqueous levels of inflammation and ischemia-related biomarkers in a spectrum of retinal ischemic conditions, including neovascular glaucoma (NVG) with stable iris neovascularization after pan retinal photocoagulation (PRP) and anti-VEGF treatment. Methods: Aqueous samples were collected from 139 eyes including NVG (n = 12), stable NVG (n = 26), CRVO (n = 11), NPDR (n = 18), PACG (n = 18), PDR (n = 25), BRVO (n = 7) and cataract (n = 22). The levels of VEGF-A, IL-8 and EPO were measured with ELISA. Results: Aqueous VEGF-A significantly decreased after anti-VEGF and PRP, from 983.79 ± 821.16 pg/ml in the NVG group (n = 11) to 256.50 ± 51.14 pg/ml in the stable NVG group (n = 24) (P = .015). Aqueous VEGF-A in stable NVG group (256.50 ± 51.14 pg/ml, n = 24) was significantly higher (ANOVA, P < .001) than in CRVO (212.10 ± 19.84 pg/ml, n = 7, P = .017), NPDR (221.18 ± 38.21 pg/ml, n = 14, P = .015), BRVO (213.14 ± 48.50 pg/ml, n = 6, P = .028) and cataract group (185.30 ± 34.35 pg/ml, n = 22, P < .001). Aqueous IL-8 in stable NVG group (74.82 ± 10.78 pg/ml, n = 24) was significantly higher (ANOVA, P < .001) than in CRVO (65.19 ± 15.34 pg/ml, n = 11, P = .032) and cataract group (54.11 ± 12.28 pg/ml, n = 22, P < .001). Aqueous EPO in stable NVG group (17.48 ± 3.02 pg/ml, n = 24) was significantly higher (ANOVA, P < .001) than in BRVO (14.98 ± 2.57 pg/ml, n = 7, P = .034) and cataract group (13.50 ± 2.65 pg/ml, n = 22, P < .001). Aqueous concentrations of VEGF-A and IL-8 correlated positively with IOP (r = 0.413, P < .001, r = 0.349, P < .001, respectively, r = correlation coefficient). VEGF-A correlated positively with IL-8 and EPO (P < .001, P = .002, respectively). IL-8 correlated positively with EPO (P < .001). Conclusions: The aqueous levels of VEGF-A, IL-8 and EPO in NVG patients with stable iris neovascularization, who had received PRP and anti-VEGF, were still significantly higher than in control groups with some retinal ischemic conditions.