Miracle-dz/UniFAR-FTUs huggingface dataset:
Robust p53 Stabilization Is Dispensable for Its Activation and Tumor Suppressor Function

Although robust p53 stabilization is critical for acute p53 responses such as DNA damage, this study underscores the important role of low basal p53 protein levels in p53 activation and tumor suppression. p53 is a short-lived protein with low basal levels under normal homeostasis conditions. However, upon DNA damage, levels of p53 dramatically increase for its activation. Although robust stabilization of p53 serves as a “trademark” for DNA damage responses, the requirement for such dramatic protein stabilization in tumor suppression has not been well addressed. Here we generated a mutant p53KQ mouse where all the C-terminal domain lysine residues were mutated to glutamines (K to Q mutations at K367, K369, K370, K378, K379, K383, and K384) to mimic constitutive acetylation of the p53 C-terminus. Because of p53 activation, p53KQ/KQ mice were perinatal lethal, yet this lethality was averted in p53KQ/− mice, which displayed normal postnatal development. Nevertheless, p53KQ/− mice died prematurely due to anemia and hematopoiesis failure. Further analyses indicated that expression of the acetylation-mimicking p53 mutant in vivo induces activation of p53 targets in various tissues without obviously increasing p53 levels. In the well-established pancreatic ductal adenocarcinoma (PDAC) mouse model, expression of the acetylation-mimicking p53-mutant protein effectively suppressed K-Ras–induced PDAC development in the absence of robust p53 stabilization. Together, our results provide proof-of-principle evidence that p53-mediated transcriptional function and tumor suppression can be achieved independently of its robust stabilization and reveal an alternative approach to activate p53 function for therapeutic purposes. Significance: Although robust p53 stabilization is critical for acute p53 responses such as DNA damage, this study underscores the important role of low basal p53 protein levels in p53 activation and tumor suppression.
Thrombospondin-4 mediates hyperglycemia- and TGF-beta-induced inflammation in breast cancer

Inflammation drives the growth of tumors and is an important predictor of cancer aggressiveness. CD68, a marker of tumor-associated macrophages (TAM), is routinely used as a marker to aid in prognosis and treatment choices for breast cancer. We report that thrombospondin-4 (TSP-4) mediates breast cancer inflammation and growth in mouse models in response to hyperglycemia and TGF-beta by increasing TAM infiltration and production of inflammatory signals in tumors. Analysis of breast cancers and non-cancerous tissue specimens from hyperglycemic patients revealed that levels of TSP-4 and of macrophage marker CD68 are upregulated in diabetic tissues. TSP-4 was co-localized with macrophages in cancer tissues. Bone-marrow-derived macrophages (BMDM) responded to high glucose and TGF-beta by upregulating TSP-4 production and expression, as well as the expression of inflammatory markers. We report a novel function for TSP-4 in breast cancer: regulation of TAM infiltration and inflammation. The results of our study provide new insights into regulation of cancer growth by hyperglycemia and TGF-beta and suggest TSP-4 as a potential therapeutic target. Novelty and Impact Thrombospondin-4 (TSP-4) is a secreted extracellular protein that belongs to the family of matricellular proteins. TSP-4 is one of the top 1% of proteins upregulated in several cancers, including breast cancer. Inflammation and infiltration of macrophages drive cancer progression and metastasis and are clinically important markers of cancer aggressiveness and critical consideration in the process of selection of the appropriate therapeutic approaches. We report that TSP-4 promotes breast cancer inflammation and infiltration of macrophages and mediates the effects of hyperglycemia and TGF-beta on cancer growth and inflammation. Our work describes a role for TSP-4 in cancer inflammation and identifies the pathways, in which increased levels of TSP-4 mediate cancer growth.
Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in Enterobacteriaceae: a Systematic Review of Current Reports

The spread of carbapenem- and polymyxin-resistant Enterobacteriaceae poses a significant threat to public health, challenging clinicians worldwide with limited therapeutic options. This review describes the current coding and noncoding genetic and transcriptional mechanisms mediating carbapenem and polymyxin resistance, respectively. ABSTRACT The spread of carbapenem- and polymyxin-resistant Enterobacteriaceae poses a significant threat to public health, challenging clinicians worldwide with limited therapeutic options. This review describes the current coding and noncoding genetic and transcriptional mechanisms mediating carbapenem and polymyxin resistance, respectively. A systematic review of all studies published in PubMed database between 2015 to October 2020 was performed. Journal articles evaluating carbapenem and polymyxin resistance mechanisms, respectively, were included. The search identified 171 journal articles for inclusion. Different New Delhi metallo-β-lactamase (NDM) carbapenemase variants had different transcriptional and affinity responses to different carbapenems. Mutations within the Klebsiella pneumoniae carbapenemase (KPC) mobile transposon, Tn4401, affect its promoter activity and expression levels, increasing carbapenem resistance. Insertion of IS26 in ardK increased imipenemase expression 53-fold. ompCF porin downregulation (mediated by envZ and ompR mutations), micCF small RNA hyperexpression, efflux upregulation (mediated by acrA, acrR, araC, marA, soxS, ramA, etc.), and mutations in acrAB-tolC mediated clinical carbapenem resistance when coupled with β-lactamase activity in a species-specific manner but not when acting without β-lactamases. Mutations in pmrAB, phoPQ, crrAB, and mgrB affect phosphorylation of lipid A of the lipopolysaccharide through the pmrHFIJKLM (arnBCDATEF or pbgP) cluster, leading to polymyxin resistance; mgrB inactivation also affected capsule structure. Mobile and induced mcr, efflux hyperexpression and porin downregulation, and Ecr transmembrane protein also conferred polymyxin resistance and heteroresistance. Carbapenem and polymyxin resistance is thus mediated by a diverse range of genetic and transcriptional mechanisms that are easily activated in an inducing environment. The molecular understanding of these emerging mechanisms can aid in developing new therapeutics for multidrug-resistant Enterobacteriaceae isolates.
What Types of Greenspaces Are Associated with Depression in Urban and Rural Older Adults? A Multilevel Cross-Sectional Study from JAGES

Depression in older adults is a public health challenge. We aimed to clarify the relationship between depression in older adults and three types of neighborhood greenspaces: trees, grasslands, and fields. We utilized data from the Japan Gerontological Evaluation Study (JAGES) performed in 2016. Multilevel logistic regression analysis was used for non-stratified and stratified analyses for the urban–rural regions. The target population comprised 126,878 older adults (age ≥ 65 years) who responded to the depression questions and were living in 881 neighborhoods in Japan. Depression was diagnosed based on a Geriatric Depression Scale score ≥5, and 20.4% of the study population had depression. In the pre-stratification analysis, areas with more greenspaces revealed lower odds of depression (odds ratio (OR) 0.95, 95% confidence interval (CI) 0.85–0.95). In urban areas, more trees correlated with lower odds of depression (OR 0.94, 95% CI 0.89–1.00). In rural areas, moderate amounts of grassland were associated with lower odds of depression compared to areas with fewer grasslands (OR 0.91, 95% CI 0.83–1.00). We found that urban areas with higher tree density and rural areas with moderate amounts of grassland were associated with lower odds of depression.
Hereditary Diffuse Gastric Cancer: A Comparative Cohort Study According to Pathogenic Variant Status

Simple Summary Pathogenic germline variants in CDH1 and CTNNA1 lead to a high prevalence of diffuse gastric cancer and breast cancer in carrier families. However, in most families with hereditary diffuse gastric cancer syndrome, the underlying genetic alteration remains elusive. In this cohort study we report on patients who met the criteria for genetic testing and compare carriers of a pathogenic CDH1/CTNNA1 variant with patients without diagnosis of a pathogenic germline variant. Gastric cancer prevalence in both groups was high and patients were diagnosed at an early age. Prevalence of breast cancer in female patients with a confirmed pathogenic variant (CDH1) was lower than previously described. Given the early age of onset in families with a suspected hereditary etiology of gastric cancer, further research is required aimed at improving clinical management and potentially the outcome in these patients. Abstract Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent (n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% (n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.
Cardiac radioablation for atrial fibrillation: target motion characterization and treatment delivery considerations.

PURPOSE The safe delivery of cardiac radioablation (CR) for atrial fibrillation (AF) is challenged by multi-direction target motion, cardiac rate variability, target proximity to critical structures, and the importance of complete target dose coverage for therapeutic benefit. Careful selection of appropriate treatment procedures is therefore essential. This work characterizes AF cardiac radioablation target motion and target proximity to surrounding structures in both healthy and AF participants to guide optimal treatment technique and technology choice. METHODS Ten healthy participants and five participants with AF underwent MRI acquisition. Multi-slice, cardiac-gated, breath-hold cines were acquired and interpolated to create 3D images for 18-30 cardiac phases. Treatment targets at the left and right pulmonary vein ostia (CTVLeft and CTVRight respectively) and adjacent cardiac structures were contoured and their displacements throughout the cardiac cycle were assessed. Target proximity to surrounding structures were measured. Free-breathing real-time 2D cine images were also acquired at 4 Hz frequency for between one- and two-minute duration. The motion of easily identifiable points within the target, diaphragm and sternum was measured to assess respiratory motion. RESULTS Target motion due to cardiac contraction was most prominent in the medial-lateral direction and of 4-5 mm magnitude. CTVRight displacements were smaller in participants with AF than healthy participants in normal sinus rhythm. Nearby cardiac structures often moved with different magnitudes and motion trajectories. CTVLeft and/or CTVRight were in direct contact with the esophagus in 73% of participants. Target motion due to respiration was most prominent in the superior-inferior direction and of 13-14 mm magnitude in both healthy and AF participants. CONCLUSION AF CR target motion and relative displacement was characterized. The combination of target motion magnitude and relative displacement to critical structures highlights the importance of personalizing motion compensation techniques for effective AF CR treatments.
[18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease

Introduction Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer. Methods Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I–II), and 13 moderate-advanced PD patients (Hoehn-Yahr III–IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [18F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings. Results [18F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% (P < 0.001). The observed pattern of reduction was posterior putamen > anterior putamen > substantia nigra pars compacta > caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations. Conclusions [18F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD.
CHANGES IN SUBFOVEAL CHOROIDAL THICKNESS AFTER INTRAVITREAL DEXAMETHASONE IMPLANT THERAPY FOR DIABETIC MACULAR EDEMA

Supplemental Digital Content is Available in the Text. After intravitreal dexamethasone implant injection for diabetic macular edema, we observed a significant decrease in subfoveal choroidal thickness and major improvements in central macular thickness and visual acuity by Weeks 7 and 14. The Subfoveal choroidal thickness reduction was significantly correlated with central macular thickness reduction, morphological features on optical coherence tomography, and vision improvement. Purpose: To investigate changes in subfoveal choroidal thickness (SFCT) and their relationship with best-corrected visual acuity and optical coherence tomography parameters after intravitreal dexamethasone implant injection for diabetic macular edema. Methods: Eighty-one eyes treated with dexamethasone implant injection for diabetic macular edema were evaluated for best-corrected visual acuity, central macular thickness, SFCT, and optical coherence tomography parameters at baseline and Weeks 7 and 14. Results: The mean baseline SFCT significantly decreased at Weeks 7 (P < 0.001) and 14 (P < 0.001). At Week 7, each 1-µm reduction in central macular thickness and five Early Treatment Diabetic Retinopathy Study letters (−0.1 logarithm of the minimal angle of resolution) improvement were associated with SFCT reductions of 0.09 (P = 0.002) and 3.91 (P = 0.044) µm, respectively. At Week 14, each 1-µm reduction in central macular thickness was associated with a 0.14-µm reduction in SFCT (P < 0.001). Eyes with good functional and anatomical responses exhibited significantly greater SFCT reductions. Subretinal fluid resulted in greater SFCT changes (P = 0.039) and better best-corrected visual acuity (P = 0.033) at Week 7. A continuous ellipsoid zone/interdigitation zone layer was associated with a smaller mean SFCT at Week 7 (P = 0.002) and better best-corrected visual acuity at Weeks 7 and 14 (both, P < 0.001). Conclusion: Changes in SFCT after dexamethasone implant injection therapy for diabetic macular edema may predict anatomical and functional outcomes and correlate with optical coherence tomography features that are known as predictors of treatment response.
The “Fortilat” Randomized Clinical Trial Follow-Up: Neurodevelopmental Outcome at 18 Months of Age

Adequate nutrition is fundamental to neonatal survival and short-term outcomes, but it also has long-term consequences on quality of life and neurologic development of preterm infants. Donkey milk has been suggested as a valid alternative for children allergic to cows’ milk proteins, due to its biochemical similarity to human milk; we, hence, hypothesized that donkey milk could be a suitable basis for developing an innovative human milk fortifier for feeding preterm infants. The aim of the current study was to extend the findings and to evaluate the neurodevelopmental outcomes at 18 months of corrected age of the infants enrolled in the clinical trial named “Fortilat”. Infants born ≤1500 g and <32 weeks of gestational age were randomized to receive either a combination of bovine milk-based multicomponent fortifier and protein supplement or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The followed fortification protocol was the same for the two groups and the two diets were designed to be isoproteic and isocaloric. All infants enrolled were included in a developmental assessment program. The neurodevelopmental assessment was performed at 18 ± 6 months of corrected age. Minor and major neurodevelopmental impairment and General Quotient (GQ) at the Griffiths-II Mental Development Scale were considered. The GQ was considered both in continuous and as two classes: lower than and higher than (or equal to) a defined cutoff (GQcl). The difference in GQ and GQcl between the two arms was estimated using Mann–Whitney–Wilcoxon test or Fischer exact test, respectively, on the assumption of casual loss at follow-up. A further analysis was performed using generalized linear models. There were 103 children (bovine milk-derived fortifier arm = 54, donkey milk-derived fortifier arm = 49) included for the neurodevelopmental follow-up. All observations were included in the interval of 18 ± 6 months of corrected age. No significant difference was observed between the two arms in the incidence of neurologic sequelae and the GQs were similar in the two arms. Our results demonstrated no difference for the donkey milk-derived fortifier compared to standard bovine-derived fortifier regarding long-term neurodevelopmental outcomes.
Alveolar Soft Part Sarcoma of Uterine Corpus in a Young Female: A Case Report With Review of Literature.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma, often occurs in adolescents and young adults with a particular predilection for the deep soft tissue of extremities. Occurrence of ASPS in the female genital tract is very uncommon and poses a significant diagnostic challenge. A case of ASPS of the uterine corpus is described in a young unmarried female, who presented to the out-patient clinic of our Institute with complaints of abnormal uterine bleeding for the past 9 mo. She was being treated with oral contraceptive pills, progesterone and tranexamic acid. Following radiological imaging and hysteroscopy, a therapeutic curettage of the lesion was done. The histopathologic features raised a differential diagnosis of a myriad of morphologic mimickers. The diagnosis was clinched by exclusion of mimickers by relevant immunohistochemical markers and strong nuclear expression of TFE3 on immunohistochemistry. The patient is on regular follow-up with oral contraceptives and antifibrinolytic medication. Despite being infrequent at this location, ASPS should be kept in differential diagnosis in young females presenting with abnormal uterine bleeding.
Survival impact and cost-effectiveness of a multidisciplinary tumor board for breast cancer in Mozambique, Sub-Saharan Africa.

BACKGROUND Despite the international endorsement of multidisciplinary tumor boards (MTBs) for breast cancer care, their implementation is sub-optimal worldwide and there is lack of evidence regarding their effectiveness in developing countries. We assessed the impact on survival and the cost-effectiveness of implementing a MTB in Mozambique, Sub-Saharan Africa. PATIENTS AND METHODS Prospective cohort study including 205 breast cancer patients diagnosed between January/2015-August/2017 (98 before/107 after MTB implementation), followed to November/2019. Pre- and post-MTB implementation subcohorts were compared for clinical characteristics, treatments and overall survival. We used hazard ratios (HRs) and 95% confidence intervals (CI), computed by Cox proportional hazards regression. The impact of MTB implementation on the cost per quality-adjusted life year (QALY) was estimated from the provider perspective. RESULTS We found no significant differences between pre- and post-MTB subcohorts regarding clinical characteristics or treatments received. Among early breast cancer patients (stage 0-III; n=163), the three-year overall survival was 48.0% (95% CI, 35.9-59.1) in the pre-MTB and 73.0% (95% CI, 61.3-81.6) in the post-MTB subcohort - adjusted hazard ratio 0.47 (95% CI, 0.27-0.81). The absolute three-year mean cost increase was 119.83 US dollars/patient and the incremental cost-effectiveness ratio was 802.96 US dollars/QALY, corresponding to 1.6 times the gross domestic product of Mozambique. CONCLUSIONS The implementation of a MTB in Mozambique led to a 53% mortality decrease among patients with early breast cancer and it was cost-effective. These findings highlight the feasibility of implementing this strategy and the need for scaling-up MTBs in developing countries, as a way to improve patient outcomes. IMPLICATIONS FOR PRACTICE Currently, more than half of the deaths from breast cancer in the world occur in developing countries. Thus, we need to develop strategies which optimize care and that are adjusted for the available resources, in order to improve the outcomes of patients with breast cancer in these regions. The discussion of cases at multidisciplinary tumor boards (MTBs) may improve survival outcomes, but their implementation is sub-optimal worldwide and there is lack of evidence regarding their effectiveness in developing countries. This study evaluated the impact of implementing a MTB on the care and survival of breast cancer patients in Mozambique, Sub-Saharan Africa and its cost-effectiveness in this low-income setting.