Miracle-dz/UniFAR-FTUs huggingface dataset:
Towards Circulating-Tumor DNA-Based Precision Medicine

In the era of precision medicine, targeted therapies have been implemented for various diseases. Genomic information guides decision-making in cancer treatment. The improvements in next-generation sequencing and polymerase chain reaction have made it possible to access the genetic information using circulating-tumor DNAs (ctDNAs). Molecular characteristics of individual tumors can be obtained by analysis of ctDNAs, thus making them excellent tools to guide decision-making during treatment. In oncology, the use of ctDNAs in clinical practice is now gaining importance. Molecular analysis of ctDNAs has potential for multiple clinical applications, including early diagnosis, prognosis of disease, prognostic and/or predictive biomarkers, and monitoring response to therapy and clonal evolution. In this paper, we highlight the applications of ctDNAs in cancer management, especially in metastatic setting, and summarize recent studies about the use of ctDNAs as predictive biomarkers for the therapeutic adaptation/response in lung cancer, breast cancer, and colorectal cancer. These studies offer the evidence to use ctDNAs as a promising approach to solve unmet clinical needs.
Type I IFN protects cancer cells from CD8+ T cell–mediated cytotoxicity after radiation

Treatment of tumors with ionizing radiation stimulates an antitumor immune response partly dependent on induction of IFNs. These IFNs directly enhance dendritic cell and CD8+ T cell activity. Here we show that resistance to an effective antitumor immune response is also a result of IFN signaling in a different cellular compartment of the tumor, the cancer cells themselves. We abolished type I IFN signaling in cancer cells by genetic elimination of its receptor, IFNAR1. Pronounced immune responses were provoked after ionizing radiation of tumors from 4 mouse cancer cell lines with Ifnar1 knockout. This enhanced response depended on CD8+ T cells and was mediated by enhanced susceptibility to T cell–mediated killing. Induction of Serpinb9 proved to be the mechanism underlying control of susceptibility to T cell killing after radiation. Ifnar1-deficient tumors had an augmented response to anti–PD-L1 immunotherapy with or without radiation. We conclude that type I IFN can protect cancer cells from T cell–mediated cytotoxicity through regulation of Serpinb9. This result helps explain why radiation of tumors can stimulate antitumor immunity yet also result in resistance. It further suggests potential targets for intervention to improve therapy and to predict responses.
Changes in salivary oxytocin levels and bonding disorder in women from late pregnancy to early postpartum: A pilot study

Objectives This pilot study aimed to 1) follow the longitudinal changes in the salivary oxytocin level of pregnant women from late pregnancy to early postpartum, 2) examine the factors related to these changes, and 3) clarify the association of these changes with mother-infant bonding. Methods This study used a longitudinal observational design and questionnaires to obtain objective and subjective data. For oxytocin evaluation, saliva samples were collected and their oxytocin levels were measured at 4-time points [i.e., 1) 36–37 gestation weeks, 2) 38–39 gestation weeks, 3) 1–2 days postpartum, 4) 4–5 days postpartum]. The oxytocin level was assayed in duplicates by enzyme-linked immunosorbent assay. Baseline data were evaluated using the Parental Bonding Instrument (25 items), State Trait Anxiety Inventory (20 items), and Center for Epidemiologic Studies Depression Scale. Postpartum data were evaluated using the Mother to Infant Bonding Scale Japanese Version (10 items), Maternity Blues Scale (13 items), and ‘Fatigue after Childbirth’ using the Visual Analogue Scale (VAS: 0–100 mm). Results The participants were 13 primiparas with a mean age of 33 years. They had no depression or anxiety at the baseline. Their mean salivary oxytocin levels significantly increased from late pregnancy (36–39 gestation weeks) up to 1 day postpartum and then decreased until 5 days postpartum. There was a negligible correlation between the bonding disorder and the salivary oxytocin level on the 5th day after childbirth. A moderate correlation was observed between the maternity blues score and the salivary oxytocin level. There was a significant negative correlation between the postpartum fatigue and the salivary oxytocin level 1 day and 5 days after childbirth. Conclusion The mean salivary oxytocin levels significantly increased from the baseline up to 1 day postpartum and then decreased until 5 days postpartum. The salivary oxytocin level was moderately associated with maternity blues and significantly with postpartum fatigue.
Increased Coffee Intake Reduces Circulating HBV DNA and HBsAg Levels in HBeAg-Negative Infection: A Cohort Study

Coffee is hepatoprotective and potentially antiviral; however, its anti-hepatitis B virus (anti-HBV) property is not known in humans. This study investigated the influence of coffee drinking behaviour as well as clinical and biochemical profiles of hepatitis B e antigen (HBeAg) negative participants on circulating HBV DNA and hepatitis B surface antigen (HBsAg) levels at a 24-week interval. Exactly 114 chronically HBV-infected adult participants were enrolled from the University of Malaya Medical Centre (UMMC), Malaysia. A significant reduction of HBV DNA level was observed in those drinking three or more cups of coffee per day, with a median reduction of 523 IU/mL (P = 0.003). Reduction of HBsAg level was observed in those drinking two cups per day, with a median reduction of 37 IU/mL (P < 0.001). Multivariate analysis showed that increased coffee intake (P = 0.015) and lower ALT level (P = 0.033) were the significant predictors for a lower HBV DNA level, whereas increased coffee intake (P = 0.002) and having a family history of HBV infection (P = 0.021) were the significant predictors for a lower HBsAg level. These data suggest that drinking three cups or more coffee per day reduces circulating HBV DNA and HBsAg levels.
α‐NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase‐4 pathway

Chemotherapy resistance is one of the most common causes of death among patients with ovarian cancer, and identifying novel antitumor agents is a priority. Here, we report that the novel molecule 2‐(anaphthoyl)ethyl‐trimethylammonium iodide (α‐NETA) induces epithelial ovarian cancer (EOC) cell pyroptosis through the gesdermin‐d (GSDMD)/caspase‐4 pathway. Furthermore, Cell Counting Kit‐8 fluorescence‐activated cell sorting analysis showed that α‐NETA treatment led to cell death in different ovarian cancer cell lines, including Ho8910, Ho8910PM, and A2780. Morphologic examination by electron microscopy indicated that cells treated with α‐NETA produced multiple microbubbles, typical of cells undergoing pyroptosis. α‐NETA also significantly increased expression of pyroptosis‐associated molecules including caspase‐4 and GSDMD in EOC cells. Knockdown of either caspase‐4 or GSDMD in ovarian cancer cells strongly interfered with α‐NETA cell‐killing activity, indicating that α‐NETA acts through the pyroptosis pathway. In vivo, α‐NETA treatment dramatically decreased the size of EOC tumors in mice. Our findings suggest that α‐NETA represents a potential new antitumor molecule or lead compound for EOC chemotherapy. —Qiao, L. , Wu, X. , Zhang, J., Liu, L. , Sui, X. , Zhang, R. , Liu, W. , Shen, F. , Sun, Y. , Xi, X. α‐NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase‐4 pathway. FASEB J. 33, 12760–12767 (2019). www.fasebj. org
Market-mediated responses confound policies to limit deforestation from oil palm expansion in Malaysia and Indonesia

Significance The rapid expansion of oil palm in Malaysia and Indonesia (M&I) has contributed to record levels of deforestation, carbon emissions, and biodiversity loss. Sustainability certification schemes seeking to address this problem have fallen short of their stated goals, leading to calls for more aggressive measures. Here we explore 3 alternative conservation policies within a global economic framework and find that market-mediated responses confound the efficacy and distributional impacts of these policies. We suggest that simply limiting palm oil production or consumption is unlikely to halt deforestation in M&I in the absence of active forest conservation incentives. We also find that M&I would benefit economically by taking domestic action rather than waiting for others to act. The global demand for palm oil has grown rapidly over the past several decades. Much of the output expansion has occurred in carbon- and biodiversity-rich forest lands of Malaysia and Indonesia (M&I), contributing to record levels of terrestrial carbon emissions and biodiversity loss. This has led to a variety of voluntary and mandatory regulatory actions, as well as calls for limits on palm oil imports from M&I. This paper offers a comprehensive, global assessment of the economic and environmental consequences of alternative policies aimed at limiting deforestation from oil palm expansion in M&I. It highlights the challenges of limiting forest and biodiversity loss in the presence of market-mediated spillovers into related oilseed and agricultural commodity and factor markets, both in M&I and overseas. Indeed, limiting palm oil production or consumption is unlikely to halt deforestation in M&I in the absence of active forest conservation incentives. Policies aimed at restricting palm oil production in M&I also have broader consequences for the economy, including significant impacts on consumer prices, real wages, and welfare, that vary among different global regions. A crucial distinction is whether the initiative is undertaken domestically, in which case the M&I region could benefit, or by major palm oil importers, in which case M&I loses income. Nonetheless, all policies considered here pass the social welfare test of global carbon dioxide mitigation benefits exceeding their costs.
Observer Agreement and Accuracy of 18F-Sodium Fluoride PET/CT in the Diagnosis of Bone Metastases in Prostate Cancer

Our aim was to evaluate the interobserver agreement in 18F-sodium fluoride (NaF) PET/CT for the detection of bone metastases in patients with prostate cancer (PCa). Methods: 18F-NaF PET/CT scans were retrieved from all patients who participated in 4 recent prospective trials. Two experienced observers independently evaluated the 18F-NaF PET/CT scans on a patient level using a 3-category scale (no bone metastases [M0], equivocal for bone metastases, and bone metastases present [M1]) and on a dichotomous scale (M0/M1). In patients with no more than 10 lesions, the location and number of lesions were recorded. On a patient level, the diagnostic performance was calculated using a sensitivity analysis, in which equivocal lesions were handled as M0 as well as M1. Results: 18F-NaF PET/CT scans from 219 patients with PCa were included, of whom 129 patients were scanned for primary staging, 67 for biochemical recurrence, and 23 for metastatic castration-resistant PCa. Agreement between the observers was almost perfect on a patient level (3-category unweighted κ = 0.83 ± 0.05, linear weighted κ = 0.90 ± 0.06, and dichotomous κ = 0.91 ± 0.07). On a lesion level (dichotomous scale), the observers agreed on the number and location of bone metastases in 205 (93.6%) patients. In the remaining 14 patients, the readers disagreed on the number of lesions in 13 patients and the location of bone metastases in 1 patient. A final diagnosis of bone metastases was made for 211 of 219 patients. The sensitivity ranged from 0.86 to 0.92, specificity from 0.83 to 0.97, positive predictive value from 0.70 to 0.93, and negative predictive value from 0.94 to 0.96. Conclusion: The interobserver agreement on 18F-NaF PET/CT for the detection of bone metastases in patients with PCa was very high among trained observers, both on a patient level and on a lesion level. Moreover, the diagnostic performance of 18F-NaF PET/CT was satisfactory, rendering 18F-NaF PET/CT a robust tool in the diagnostic armamentarium.
Significant Correlation Between Grip Strength and m2bpgi in Patients with Chronic Liver Diseases

We sought to compare the impact upon grip strength (GS) between the Mac-2 binding protein glycosylation isomer (M2BPGi) and the Fibrosis-4 (FIB4) index in chronic liver disease (CLD) patients (n = 376: 171 males and 205 females, and 137 liver cirrhosis (LC) cases (36.4%)). Factors linked to the low GS (<26 kg in male and <18 kg in female) were also investigated using univariate and multivariate analyses. The median GS in males was 35.5 kg, while that in females was 21.1 kg. The median M2BPGi was 1.11 cutoff index, whereas the median FIB4 index was 2.069. In both male (P < 0.0001) and female (P = 0.0001), GS in LC patients was significantly lower than that in non-LC patients. In males, M2BPGi (r = −0.4611, P < 0.0001) and the FIB4 index (r = −0.4556, P < 0.0001) significantly correlated with GS. Similarly, in females, M2BPGi (r = −0.33326, P < 0.0001) and our FIB4 index (r = −0.26388, P = 0.0001) also significantly correlated with GS. In the multivariate analyses of factors linked to the low GS, independent factors were: M2BPGi (P = 0.0003) and skeletal muscle index (P = 0.0007) in males, and age (P < 0.0001) and serum albumin level (P = 0.0484) in females. In conclusion, liver fibrosis markers were well-correlated with GS in CLD patients. In particular, M2BPGi can be helpful for predicting the low GS in male patients.
Nutritional Characteristics and Antimicrobial Activity of Australian Grown Feijoa (Acca sellowiana)

The present study determined the chemical composition, bioactive compounds and biological properties of Australian grown feijoa (Acca sellowiana), including whole fruit with peel, fruit peel and pulp, in order to assess the nutritional quality and antimicrobial activity of this emerging subtropical fruit. Polyphenolic compounds and vitamins were determined by UHPLC-PDA-MS/MS, showing that the feijoa fruit not only contains high amounts of antioxidant flavonoids, but is also a valuable source of vitamin C (63 mg/100 g FW (fresh weight)) and pantothenic acid (0.2 mg/100 g FW). Feijoa fruit is also a good source of dietary fibre (6.8 g/100 g FW) and potassium (255 mg/100 g FW). The edible fruit peel possesses significantly (p < 0.05) higher amounts of antioxidant flavonoids and vitamin C than the fruit pulp. This is most likely the reason for the observed strong antimicrobial activity of the peel-extracts against a wide-range of food-spoilage microorganism. The consumption of feijoa fruit can deliver a considerable amount of bioactive compounds such as vitamin C, flavonoids and fibre, and therefore, may contribute to a healthy diet. Furthermore, the potential use of feijoa-peel as a natural food perseverative needs to be investigated in follow-up studies.
The Experiences of People Living with Peripheral Neuropathy in Kuwait—A Process Map of the Patient Journey

Peripheral neuropathy is a neurological disease characterised by pain, numbness, tingling, swelling or muscle weakness due to nerve damage, caused by multiple factors such as trauma, infections and metabolic diseases such as diabetes. In Kuwait 54% of the diabetic population, has peripheral neuropathy. In this exploratory, qualitative study conducted in Kuwait, 25 subjects with peripheral neuropathy took part in one-on-one, semi-structured interviews lasting 45–60 min. Interviews were transcribed, translated into English and coded using NVivo 12. Four individual patient journeys were mapped out in detail, then compared and condensed into a single process map. The remaining 21 interviews were then reviewed to ensure the final map represented all patient journeys. Participants reported similar healthcare pathways for their peripheral neuropathy and faced various difficulties including lack of psychological support, administrative issues (long waiting referral periods, loss of medical documents, shortage of specialists and lack of centralized electronic medical records) and inadequate medical care (shortage of new treatments and deficient follow-ups). Mapping the patient journey in Kuwait showed similar pharmacological treatment to UK guidelines, except that some medicines were unavailable. The map also indicated the need for an integrated referral approach, the use of technology for electronic medical recording and report transmission, alongside education on self-management, coping mechanisms and treatment options for people living with peripheral neuropathy.
The MyMOMA domain of MYO19 encodes for distinct Miro-dependent and Miro-independent mechanisms of interaction with mitochondrial membranes

MYO19 interacts with mitochondria through a C-terminal membrane association domain (MyMOMA). The specific mechanisms for localization of MYO19 to mitochondria are poorly understood. Using new promiscuous biotinylation data in combination with existing affinity-capture databases, we have identified a number of putative MYO19-interacting proteins. We chose to further explore the interaction between MYO19 and the mitochondrial GTPase Miro2 by expressing mchr-Miro2 in combination with GFP-tagged fragments of the MyMOMA domain and assaying for recruitment of MYO19-GFP to mitochondria. Co-expression of MYO19898-970-GFP with mchr-Miro2 enhanced MYO19898-970-GFP localization to mitochondria. Mislocalizing Miro2 to filopodial tips or the cytosolic face of the nuclear envelope did not recruit MYO19898-970-GFP to either location. To address the kinetics of the Miro2/MYO19 interaction, we used FRAP analysis and permeabilization-activated reduction in fluorescence (PARF) analysis. MyMOMA constructs containing a putative membrane insertion motif but lacking the Miro2-interacting region displayed slow exchange kinetics. MYO19898-970-GFP, which does not include the membrane-insertion motif, displayed rapid exchange kinetics, suggesting that the MYO19 interacting with Miro2 has higher mobility than MYO19 inserted into the mitochondrial outer membrane. Mutation of well-conserved, charged residues within MYO19 or within the switch I and II regions of Miro2 abolished the enhancement of MYO19898-970-GFP localization in cells ectopically expressing mchr-Miro2. Additionally, expressing mutant versions of Miro2 thought to represent particular nucleotide states indicated that the enhancement of MYO19898-970-GFP localization is dependent on Miro2 nucleotide state. Taken together, these data suggest that membrane-inserted MYO19 is part of a larger complex, and that Miro2 plays a role in integration of actin- and microtubule-based mitochondrial activities.
Mechanisms of reactivation of latent tuberculosis infection due to SIV co-infection.

HIV is a major driver of Tuberculosis (TB) reactivation. Depletion of CD4+ T cells is assumed to be the basis behind TB reactivation in individuals with latent tuberculosis Infection (LTBI) co-infected with human immunodeficiency virus (HIV). Non-human primates (NHPs) coinfected with a mutant simian immunodeficiency virus (SIVΔGY), that does not cause depletion of tissue CD4+ T cells during infection, failed to reactivate TB. To investigate the contribution of CD4+ T cell depletion relative to other mechanisms of SIV-induced reactivation of LTBI, we used CD4R1 antibody to deplete CD4+ T cells in animals with LTBI without lentiviral infection. We showed that the mere depletion of CD4+ T cells during LTBI was insufficient in generating reactivation of LTBI. Instead, direct cytopathic effects of SIV resulting in chronic immune activation, along with the altered effector T cell phenotypes and dysregulated T cell homeostasis, were likely mediators of reactivation of LTBI. These results revealed important implications for controlling TB in the HIV co-infected individuals.
Impact of Endometriomas and Deep Infiltrating Endometriosis on Pregnancy Outcomes and on First and Second Trimester Markers of Impaired Placentation

Background and objective: Previous studies did not draw a definitive conclusion about the influence of the role of deep endometriosis (DE) and ovarian endometrioma (OE) as risk factor for developing adverse perinatal outcomes in patients affected by endometriosis. This study aimed to investigate if adverse fetal and maternal outcomes, and in particular the incidence of small for gestational age (SGA) infants, are different in pregnant women with OE versus pregnant women with DE without OE. Material and methods: This study was based on a retrospective analysis of a database collected prospectively. The population included in the study was divided into three groups: patients with OE, patients with DE without concomitant OE, and patients without endometriosis (controls). The controls were matched on the basis of age and parity. Demographic data at baseline and pregnancy outcomes were recorded. Results: There was no statistically significant difference in first trimester levels of PAPP-A, first and mid-pregnancy trimester mean Uterine Artery Doppler pulsatile index, estimated fetal weight centile, and SGA fetuses’ prevalence for patients with OE, and those with DE without OE in comparison to health women; moreover, there was no statistically significant difference with regard to SGA birth prevalence, prevalence of preeclampsia, and five-minute Apgar score between these three groups. Conclusions: The specific presence of OE or DE in pregnant women does not seem to be associated with an increased risk of delivering an SGA infant. These data seem to suggest that patients with endometriosis should be treated in pregnancy as the general population, thus not needing a closer monitoring.
A Prognostic Model for the Outcome of Nobel Biocare Dental Implants with Peri-Implant Disease after One Year

Background: This investigation, based on a 1-year retrospective cohort study, aimed to estimate and validate a prognostic model for ailing and failing implants due to peri-implant disease. Methods: A total of 240 patients (male: 97; female: 143; average age of 57.3 years) with at least one ailing or failing implant were included: 120 patients for model derivation and 120 patients for model validation. The primary outcome measure was the implant status: success, defined as the arrest of the disease, or failure defined as implant extraction, prevalence or re-incidence of peri-implant disease). Potential prognostic risk indicators were collected at the baseline evaluation. The relative risk (RR) was estimated for the predictors through logistic regression and the c-statistic (95% confidence interval) was calculated for both derivation and validation sets. The significance level was set at 5%. Results: The risk model retrieved the prognostic factors age (RR = 1.04), history of Periodontitis (RR = 3.13), severe peri-implant disease status (RR = 3.26), implant length (RR = 3.52), early disease development (RR = 3.99), with good discrimination in both the derivation set (0.763 [0.679; 0.847]) and validation set (0.709 [0.616; 0.803]). Conclusions: A prognostic risk model for estimating the outcome of implants with peri-implant disease is available, with a good performance considering the c-statistic evaluation.