Miracle-dz/UniFAR-FTUs huggingface dataset:
RET fusion in advanced non-small-cell lung cancer and response to cabozantinib

Rationale: Lung cancer is a series of gene-driven disease. EGFR, ALK, and ROS1 are 3 major driver genes that play an important role in lung cancer development and precision management. Additionally, rare genetic alterations continue to be discovered and may become novel targets for therapy. The RET gene is one of such rare genetic alteration of non-small cell lung cancer (NSCLC). In this report, we present a RET-positive case that benefited from cabozantinib treatment. Patient concern: A 50-year-old male patient was diagnosed with lung adenocarcinoma 2 years ago, at that time he received palliative surgery of pulmonary carcinoma and completed 4 cycles of chemotherapy with gemcitabine and cisplatin. Six months later, he was hospitalized in our cancer center due to the disease recurrence, presenting with pleural metastasis. Diagnosis: Gene alteration was examined using the intraoperative specimen by PCR method, and KIF5B/RET gene fusion was detected. Therefore, the patient was diagnosed with late-stage lung adenocarcinoma with RET gene mutation. Interventions: The patient received treatment with cabozantinib from June 2017. Outcomes: Cabozantinib was administered (140 mg orally, once daily) for approximate 9 months, and his disease achieved stable disease (SD). During that period, there were no severe adverse events (AE), except for a grade II rash (CTCAE 4.0). Lessons: We found that the RET fusion gene is a novel driver molecular of lung adenocarcinoma in patients without common mutations in such genes as EGFR, ALK, and ROS1. This case report supports a rationale for the treatment of lung adenocarcinoma patients with a RET fusion and provides alternative treatment options for these types of NSCLC patients.
Enterococcus faecalis Countermeasures Defeat a Virulent Picovirinae Bacteriophage

Enterococcus faecalis is an opportunistic pathogen that has emerged as a major cause of nosocomial infections worldwide. Many clinical strains are indeed resistant to last resort antibiotics and there is consequently a reawakening of interest in exploiting virulent phages to combat them. However, little is still known about phage receptors and phage resistance mechanisms in enterococci. We made use of a prophageless derivative of the well-known clinical strain E. faecalis V583 to isolate a virulent phage belonging to the Picovirinae subfamily and to the P68 genus that we named Idefix. Interestingly, most isolates of E. faecalis tested—including V583—were resistant to this phage and we investigated more deeply into phage resistance mechanisms. We found that E. faecalis V583 prophage 6 was particularly efficient in resisting Idefix infection thanks to a new abortive infection (Abi) mechanism, which we designated Abiα. It corresponded to the Pfam domain family with unknown function DUF4393 and conferred a typical Abi phenotype by causing a premature lysis of infected E. faecalis. The abiα gene is widespread among prophages of enterococci and other Gram-positive bacteria. Furthermore, we identified two genes involved in the synthesis of the side chains of the surface rhamnopolysaccharide that are important for Idefix adsorption. Interestingly, mutants in these genes arose at a frequency of ~10−4 resistant mutants per generation, conferring a supplemental bacterial line of defense against Idefix.
The CAT-262 C>T, MnSOD Ala16Val, GPX1 Pro198Leu Polymorphisms Related to Oxidative Stress and the Presence of Gastric Lesions.

BACKGROUND AND AIMS The increased oxidative stress plays an important role in gastro-duodenal ulcers and gastric cancer occurrence. We investigated the association between the genetic polymorphisms of genes encoding the antioxidative enzymes CAT, GPX and SOD and the occurrence of gastric lesions, considering also the environmental risk factors such as H. pylori infection, drug exposure, smoking and alcohol consumption. METHODS We included 373 patients who underwent endoscopy for symptoms, anemia or bleeding investigation. A complete set of demographical, clinical and pathological data was recorded. All patients were successfully genotyped. RESULTS In the multivariate logistic regression model, the patients having Pro/Pro genotype of GPX1 gene polymorphism had more severe gastric lesions as compared with patients with the Leu/Pro or Leu/Leu genotype (OR= 1.89, 95%CI: 0.99-3.57, p=0.051). The GPX1 Pro198Leu and the MnSOD Ala16Val gene polymorphism could be independent risk factors for reactive gastropathy changes, as shown by their association very close to statistical significance (p=0.059 and p=0.054, respectively). Consumption of anticoagulants was a significant independent predictor (p=0.023, OR:0.43 95%CI:0.21-0.89) for the absence of active gastritis, while low-dose aspirin consumption was a risk factor for active gastritis in biopsy samples (p=0.025, OR:1.71, 95%CI:1.07-2.74). CONCLUSION The variant genotype of GPX1Pro198Leu was associated with an increased risk for reactive gastropathy changes in gastric biopsies and with less severe endoscopic lesions, while MnSODAla16Val variant genotype (Val/Val or Val/Ala) seems to be related to the reactive gastropathy. However, none of them were associated with inflammatory or premalignant gastric lesions.
A recycling anti-transferrin receptor-1 monoclonal antibody as an efficient therapy for erythroleukemia through target up-regulation and antibody-dependent cytotoxic effector functions

ABSTRACT Targeting transferrin receptor 1 (TfR1) with monoclonal antibodies is a promising therapeutic strategy in cancer as tumor cells often overexpress TfR1 and show increased iron needs. We have re-engineered six anti-human TfR1 single-chain variable fragment (scFv) antibodies into fully human scFv2-Fcγ1 and IgG1 antibodies. We selected the more promising candidate (H7), based on its ability to inhibit TfR1-mediated iron-loaded transferrin internalization in Raji cells (B-cell lymphoma). The H7 antibody displayed nanomolar affinity for its target in both formats (scFv2-Fcγ1 and IgG1), but cross-reacted with mouse TfR1 only in the scFv2-Fc format. H7 reduced the intracellular labile iron pool and, contrary to what has been observed with previously described anti-TfR1 antibodies, upregulated TfR1 level in Raji cells. H7 scFv2-Fc format elimination half-life was similar in FcRn knock-out and wild type mice, suggesting that TfR1 recycling contributes to prevent H7 elimination in vivo. In vitro, H7 inhibited the growth of erythroleukemia and B-cell lymphoma cell lines (IC50 0.1 µg/mL) and induced their apoptosis. Moreover, the Im9 B-cell lymphoma cell line, which is resistant to apoptosis induced by rituximab (anti-CD20 antibody), was sensitive to H7. In vivo, tumor regression was observed in nude mice bearing ERY-1 erythroleukemia cell xenografts treated with H7 through a mechanism that involved iron deprivation and antibody-dependent cytotoxic effector functions. Therefore, targeting TfR1 using the fully human anti-TfR1 H7 is a promising tool for the treatment of leukemia and lymphoma.
The effect of sodium butyrate and cisplatin on expression of EMT markers

Histone modifications play a key role in the epigenetic regulation of gene transcription in cancer cells. Histone acetylations are regulated by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are increased in ovarian carcinomas and they are involved in carcinogenesis and resistance to chemotherapeutic agents. In our study we investigated anticancer effect of HDAC inhibitor sodium butyrate (NaBu) on cisplatin-sensitive and cisplatin-resistant ovarian cell lines A2780 and A2780cis. A2780 and A2780cis were treated with NaBu alone or in combination with cisplatin (CP). NaBu inhibited the growth of both cell lines and enhanced cytotoxic effect of CP. Exposure to NaBu for 24 h induced cell cycle arrest. The expressions of EMT-related genes and proteins were further investigated by qPCR and western blot analysis. Loss of E-cadherin has been shown to be crucial in ovarian cancer development. We found that NaBu dramatically induce expression of E-cadherin gene (CDH1) and protein levels in A2780 and A2780cis. We investigated correlation between transcription and methylation of CDH1gene. Methylation level analysis in 32 CpG sites in CDH1 gene (promoter/exon1 regions) was performed using bisulfite NGS (Next Generation Sequencing). We found that cisplatin-resistant cell line A2780cis cells differ from their cisplatin-sensitive counterparts in the CDH1 methylation. Methylation in A2780cis cells is elevated compared to A2780. However, NaBu-induced expression of CDH1 was not accompanied by CDH1 demethylation. NaBu treatment induced changes in expression of EMT-related genes and proteins. Interestingly E-cadherin zinc finger transcriptional repressor SNAIL1 was upregulated in both cell lines. Mesenchymal marker vimentin was downregulated. Matrix metalloproteases (MMPs) are necessary for pericellular proteolysis and facilitate migration and invasion of tumour cells. NaBu induced mRNA expression of MMPs, mild changes in activities of gelatinases MMP2 and MMP9 were detected. Our data demonstrate that NaBu sensitizes cisplatin-resistant ovarian cancer cells, re-established E-cadherin expression, but it was not able to reverse the EMT phenotype completely.
ollision-induced dissociation of protonated nanodroplets

Protonated nanodroplets are easily generated using electrospray ionization mass spectrometry (ESI–MS) and may be isolated and fragmented using collision-induced dissociation (CID), causing sequential loss of water molecules. These studies reveal not only the expected high stability of the “magic” protonated water cluster [H(H2O)21], a dodecahedral clathrate cage, but also a new, rather more subtle trend in stabilities of product ions that manifests itself as increased stability of clusters that have a multiple of 12–13 water vailable online 17 October 2008
Feasibility of a Low-Intensity, Technology-Based Intervention for Increasing Physical Activity in Adults at Risk for a Diabetic Foot Ulcer: A Mixed-Methods Study

Background: Among adults with diabetes, 19-34% will develop a diabetic foot ulcer (DFU), which increases amputation risk and health care costs, and worsens quality of life. Regular physical activity, when increased gradually, may help prevent DFUs. In this mixed-methods study, we examined the feasibility of a low-intensity, technology-based behavioral intervention to increase activity in adults at risk for DFUs. Method: Participants at risk for a DFU (n = 12; 66% female; mean age = 59.9 years) received four in-person exercise and behavioral counseling sessions over 2-3 weeks, supplemented with use of an activity monitor (to track steps) and text messages (to reinforce behavioral strategies) for an added 8 weeks. Pre- and postintervention assessments of accelerometer measured activity, daily mobility, and glycemic control (A1C) were completed. Treatment acceptability was assessed by questionnaire and via key informant interview. Results: The program appears feasible since all but one participant attended all four sessions, all used the activity monitor and all responded to text messages. Treatment acceptability (scale: 1 = very dissatisfied, 5 = extremely satisfied) was high; average item ratings were 4.79 (SD = 0.24). Participants increased their steps by an average of 881.89 steps/day (d = 0.66). A1C decreased on average by 0.33% (d = 0.23). Daily mobility did not change. Interview results suggest that participants perceived benefits from the intervention. Participant recommended improvements included providing more physical activity information, addressing pain, and intervention delivery in a podiatry clinic. Conclusion: Individuals at risk for a DFU might benefit from a minimally intensive, technology-based intervention to increase their physical activity. Future research comparing the intervention to usual care is warranted.
Factors Affecting Clinical and Endoscopic Outcomes of Placebo Arm in Trials of Biologics and Small Molecule Drugs in Ulcerative Colitis: A Meta-Analysis.

BACKGROUND Previous systematic cumulative analyses of the placebo arm in ulcerative colitis (UC) were limited by the wide heterogeneity in the scores and definitions of response. We aimed at estimating the placebo rates of remission, response, and mucosal healing (MH) in phase 2 and 3 randomized placebo-controlled trials of biologics and small molecule drugs that used homogeneous criteria for the assessment of outcomes. METHODS PubMed Central, Embase, and reference lists of articles were systematically searched through July 2017. Only studies that employed the Mayo score were included. RESULTS Thirty-one randomized placebo-controlled trials consisting of 2702 patients met the inclusion criteria. At induction, the pooled estimates of the placebo rates of remission, response, and MH were 9% (95% confidence interval [CI], 7%-12%; range: 0%-29%; I2 = 75.0%), 34% (95% CI, 31%-38%; range: 12%-75%; I2 = 61.3%), and 26% (95% CI, 22%-30%; range: 2%-65%; I2 = 77.7%), respectively. At maintenance, the pooled estimates of the placebo rates of remission, response, and MH were 14% (95% CI, 10%-18%; range: 6%-30%; I2 = 73.0%), 23% (95% CI, 20%-27%; range: 18%-36%; I2 = 53.0%), and 19% (95% CI, 15%-23%; range: 12%-30%; I2 = 65.0%), respectively. Among the variables assessed by logistic regression analysis, multiple factors influenced the outcomes of placebo arms, including concomitant systemic steroids at baseline, endoscopic central reading, being naïve or non-naïve to anti-TNFs, and disease duration. CONCLUSIONS Despite the wide use of homogeneous criteria for the assessment of clinical and endoscopic outcomes, a high heterogeneity among placebo arms of modern trials in UC still exists.
Association Between Plasma Neutrophil Gelatinase‐Associated Lipocalin and Cardiac Disease Hospitalizations and Deaths in Older Women

Background Neutrophil gelatinase‐associated lipocalin (NGAL) or lipocalin 2 may promote atherosclerosis and plaque instability leading to increased risk of cardiac events. We investigated the relationships between plasma NGAL, cardiovascular disease biomarkers, and long‐term cardiac events. Methods and Results The study population consisted of 1131 ambulant older white women (mean age 75 years) without clinical coronary heart disease (CHD) and measures of plasma NGAL in the Perth Longitudinal Study of Ageing Women with 14.5‐year CHD and heart failure hospitalizations or death (events) captured using linked records. Over 14.5 years, 256 women had CHD events, while 118 had heart failure events. Per SD increase in log‐transformed NGAL there was a 35% to 37% increase in relative hazards for CHD and heart failure events in unadjusted analyses, which remained significant after adjustment for conventional risk factors for CHD events (hazard ratio 1.29, 95% CI 1.13–1.48, P<0.001) but not heart failure (P>0.05). Women in the highest 2 quartiles of NGAL had higher relative hazards for CHD events compared with women in the lowest quartile hazard ratio 1.61, 95% CI 1.08–2.39, P=0.019 and hazard ratio 1.97, 95% CI 1.33–3.93, P=0.001, respectively. These associations were independent of high‐sensitivity cardiac troponin I, homocysteine, and estimated renal function. NGAL correctly reclassified 1 in 4 women who sustained a CHD event up in risk and 1 in 10 women without CHD events down in risk. Conclusions NGAL was associated with increased risk of long‐term CHD events, independent of conventional risk factors and biomarkers. These findings provide mechanistic insight into the role of NGAL with cardiac events.
Weighted causal inference methods with mismeasured covariates and misclassified outcomes

Inverse probability weighting (IPW) estimation has been widely used in causal inference. Its validity relies on the important condition that the variables are precisely measured. This condition, however, is often violated, which distorts the IPW method and thus yields biased results. In this paper, we study the IPW estimation of average treatment effects for settings with mismeasured covariates and misclassified outcomes. We develop estimation methods to correct for measurement error and misclassification effects simultaneously. Our discussion covers a broad scope of treatment models, including typically assumed logistic regression models and general treatment assignment mechanisms. Satisfactory performance of the proposed methods is demonstrated by extensive numerical studies.
CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

ABSTRACT Aberrant expression of CUL4B was identified in various types of solid cancers. Cumulative evidences support the oncogenic role of CUL4B in cancers, including regulation of cell proliferation and signal transduction. However, its clinical value and potential pathogenic mechanism in diffuse large B-cell lymphoma (DLBCL) have not been described previously. Therefore, we hypothesize that overexpressed CUL4B may contribute to the pathogenesis of DLBCL. The aim of this study is to assess the expression and the biological function of CUL4B in DLBCL progression. In our study, CUL4B overexpression was observed in DLBCL tissues, and its upregulation was closely associated with poor prognosis in patients. Furthermore, the functional roles of CUL4B was detected both in vitro and in vivo. We demonstrated that silencing CUL4B could not only induce cell proliferation inhibition, cell cycle arrest, and motility attenuation of DLBCL cells in vitro, but also decrease tumor growth in DLBCL xenografts mice. In addition, we identiﬁed that CUL4B may act as a potent inductor of JNK phosphorylation in regulation of autophagy. Our findings demonstrated a significant role of CUL4B in the development and progression of DLBCL. CUL4B may act as a useful biomarker and a novel therapeutic target in DLBCL.
Mindfulness, Experiential Avoidance, and Recovery From Hematopoietic Stem Cell Transplantation.

Background Mood disturbance, pain, and fatigue are prevalent and distressing concerns for patients with hematologic cancer recovering from hematopoietic stem cell transplantation (HSCT). The way in which individuals approach difficult thoughts and emotions may affect symptoms and functioning. Specifically, mindfulness has been associated with more optimal psychological and physical functioning, whereas experiential avoidance has been associated with poorer outcomes. Purpose The primary objective was to determine whether mindfulness and experiential avoidance measured prior to HSCT were associated with recovery of psychological and physical functioning following HSCT. We also evaluated dimensions of mindfulness to determine which were most robustly associated with outcomes. Methods Participants completed measures of mindfulness and experiential avoidance prior to HSCT. Depression and anxiety symptoms and pain and fatigue interference with daily activities were assessed prior to HSCT and 1, 3, and 6 months post-HSCT. Results Participants who reported better ability to describe their internal experiences and who were better able to act with awareness experienced less depression, anxiety, and fatigue interference following HSCT. Participants who were nonjudgmental and nonreactive toward thoughts and emotions experienced less depression and anxiety following HSCT, but these traits were not associated with pain or fatigue interference. Being a good observer of internal experiences was not associated with outcomes, nor was experiential avoidance. Conclusions Results suggest that most facets of mindfulness may optimize psychological functioning following HSCT, and the ability to describe one's internal experience and to focus on the present moment may have a beneficial influence on physical functioning.
Temporal trends of legacy and emerging persistent organic pollutants in inuit preschoolers from Northern Quebec (Canada)

ABSTRACT In this study, we report the temporal trends of persistent organic pollutants (POPs) in 181 preschool Inuit children from Nunavik and the influence of confounding factors on blood contaminant levels. From 2006 to 2010, no significant trends were detected in Σpolychlorinated biphenyls (ΣPCBs), Σorganochlorine pesticides (ΣOPs), Σtoxaphene, and Σper- and polyfluoroalkyl substances (ΣPFASs). On the contrary, significant downward trends ranging from 9.3% to 14.3% per year were found for polybrominated diphenyl ethers (PBDEs). Breastfeeding was significantly associated with increased levels of POPs. Age was positively and significantly related to ΣPCBs, ΣOPs and Σtoxaphene. Compared with girls, boys had significantly higher concentrations of ΣPBDEs, but lower concentrations of ΣPFASs. Weight-for-height or body mass index z-scores were negatively and significantly related to ΣPCBs and ΣOPs. Passive smoking was positively and significantly associated with ΣOPs and Σtoxaphene. In conclusion, continued efforts to reduce contaminant exposure are needed to protect children’s health and development.
Selective Strengthening of Intracortical Excitatory Input Leads to Receptive Field Refinement during Auditory Cortical Development

In the primary auditory cortex (A1) of rats, refinement of excitatory input to layer (L)4 neurons contributes to the sharpening of their frequency selectivity during postnatal development. L4 neurons receive both feedforward thalamocortical and recurrent intracortical inputs, but how potential developmental changes of each component can account for the sharpening of excitatory input tuning remains unclear. By combining in vivo whole-cell recording and pharmacological silencing of cortical spiking in young rats of both sexes, we examined developmental changes at three hierarchical stages: output of auditory thalamic neurons, thalamocortical input and recurrent excitatory input to an A1 L4 neuron. In the thalamus, the tonotopic map matured with an expanded range of frequency representations, while the frequency tuning of output responses was unchanged. On the other hand, the tuning shape of both thalamocortical and intracortical excitatory inputs to a L4 neuron became sharpened. In particular, the intracortical input became better tuned than thalamocortical excitation. Moreover, the weight of intracortical excitation around the optimal frequency was selectively strengthened, resulting in a dominant role of intracortical excitation in defining the total excitatory input tuning. Our modeling work further demonstrates that the frequency-selective strengthening of local recurrent excitatory connections plays a major role in the refinement of excitatory input tuning of L4 neurons. SIGNIFICANCE STATEMENT During postnatal development, sensory cortex undergoes functional refinement, through which the size of sensory receptive field is reduced. In the rat primary auditory cortex, such refinement in layer (L)4 is mainly attributed to improved selectivity of excitatory input a L4 neuron receives. In this study, we further examined three stages along the hierarchical neural pathway where excitatory input refinement might occur. We found that developmental refinement takes place at both thalamocortical and intracortical circuit levels, but not at the thalamic output level. Together with modeling results, we revealed that the optimal-frequency-selective strengthening of intracortical excitation plays a dominant role in the refinement of excitatory input tuning.