Silencing of human DNA polymerase λ causes replication stress and is synthetically lethal with an impaired S phase checkpoint

Human DNA polymerase (pol) λ functions in base excision repair and non-homologous end joining. We have previously shown that DNA pol λ is involved in accurate bypass of the two frequent oxidative lesions, 7,8-dihydro-8-oxoguanine and 1,2-dihydro-2-oxoadenine during the S phase. However, nothing is known so far about the relationship of DNA pol λ with the S phase DNA damage response checkpoint. Here, we show that a knockdown of DNA pol λ, but not of its close homologue DNA pol β, results in replication fork stress and activates the S phase checkpoint, slowing S phase progression in different human cancer cell lines. We furthermore show that DNA pol λ protects cells from oxidative DNA damage and also functions in rescuing stalled replication forks. Its absence becomes lethal for a cell when a functional checkpoint is missing, suggesting a DNA synthesis deficiency. Our results provide the first evidence, to our knowledge, that DNA pol λ is required for cell cycle progression and is functionally connected to the S phase DNA damage response machinery in cancer cell

Firm size distribution and employment fluctuations:Theory and evidence

This paper studies the effect of the firm-size distribution on the relationship between employment and output. We construct a theoretical model, which predicts that changes in demand for industry output have larger effects on employment in industries characterised by a distribution that is more skewed towards smaller firms. Industry-specific shape parameters of the firm size distributions are estimated using firm-level data from Germany, Sweden and the UK, and used to augment a relationship between industry-level employment and output. Our empirical results align with the predictions of the theory and confirm that the size distribution of firms is an important determinant of the relationship between changes in output and employment

Update of the statements on biology and clinical impact of occult hepatitis B virus infection

Summary In October 2018 a large number of international experts with complementary expertise came together in Taormina to participate in a workshop on occult hepatitis B virus infection (OBI). The objectives of the workshop were to review the existing knowledge on OBI, to identify issues that require further investigation, to highlight both existing controversies and newly emerging perspectives, and ultimately to update the statements previously agreed in 2008. This paper represents the output from the workshop

Increased FGF23 serum level is associated with unstable carotid plaque in type 2 diabetic subjects with internal carotid stenosis.

BACKGROUND: The object of this study was to investigate the potential role of FGF23 on plaque stability in type 2 diabetic patients with internal carotid artery stenosis. METHODS: In this retrospective observational study, we analyzed FGF23 serum level in 361 type 2 diabetic patients with internal carotid artery stenosis undergoing carotid endarterectomy and in 598 diabetic controls without carotid atherosclerosis. RESULTS: We found that FGF23 median serum levels was significantly higher in patients than in diabetic controls [67.7 (59.5-77.8) pg/mL and 43.89 (37.5-50.4), P < 0.001] and was significantly and independently associated with unstable plaque in patients with internal carotid artery stenosis [OR, 5,71 (95% CI, 2.09-15.29]. CONCLUSIONS: We have found, for the first time, that FGF23 could be associated with unstable plaque in type 2 diabetic patients with internal carotid artery stenosis

Multiple thromboembolism with multiple causes in a 69-year-old woman: a case report

<p>Abstract</p> <p>Introduction</p> <p>Aggressive, recurrent embolisms require accurate etiologic diagnosis. We describe the case of a 69-year-old Italian Caucasian woman with recurrent arterial embolisms in whom several sources and triggers of thrombosis were detected.</p> <p>Case presentation</p> <p>The patient, a 69-year-old Italian Caucasian woman, presented with a systemic embolism that was initially attributed to atrial fibrillation. The recurrence of embolisms despite anti-thrombotic therapy prompted a re-evaluation of the clinical presentation. New potential causes of thrombosis emerged in this patient, including thrombocytosis associated with the <it>JAK2 V617F </it>mutation and the very rare mural thrombosis of the descending aorta. A mural thrombus in the pulmonary artery was detected contiguous with the aortic mural thrombosis, raising the possibility of a clinically silent ductus Botalli as the initiating event. The patient was treated with warfarin, aspirin, hydroxyurea, and surgery.</p> <p>Conclusions</p> <p>The diagnosis was achieved via systematic use of imaging procedures and reconsideration of blood tests performed to explore the diagnosis of thrombosis. This allowed a deeper and more detailed analysis of the case beyond the conventional approach, which would have aimed to identify one cause for the condition at hand, in this case, atrial fibrillation. The broader approach that we used resulted in the diagnosis of multiple embolisms from multiple sites and multiple causes.</p

A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres.

Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol λ) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol λ, strongly affects the survival of ALT cells. In vitro, Pol λ can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol λ. Pol λ associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol λ in the maintenance of telomeres by the ALT mechanism

Effect of Lactoferrin on Clinical Outcomes of Hospitalized Patients with COVID-19: The LAC Randomized Clinical Trial

: As lactoferrin is a nutritional supplement with proven antiviral and immunomodulatory abilities, it may be used to improve the clinical course of COVID-19. The clinical efficacy and safety of bovine lactoferrin were evaluated in the LAC randomized double-blind placebo-controlled trial. A total of 218 hospitalized adult patients with moderate-to-severe COVID-19 were randomized to receive 800 mg/die oral bovine lactoferrin (n = 113) or placebo (n = 105), both given in combination with standard COVID-19 therapy. No differences in lactoferrin vs. placebo were observed in the primary outcomes: the proportion of death or intensive care unit admission (risk ratio of 1.06 (95% CI 0.63-1.79)) or proportion of discharge or National Early Warning Score 2 (NEWS2) ≤ 2 within 14 days from enrollment (RR of 0.85 (95% CI 0.70-1.04)). Lactoferrin showed an excellent safety and tolerability profile. Even though bovine lactoferrin is safe and tolerable, our results do not support its use in hospitalized patients with moderate-to-severe COVID-19

The association of indwelling urinary catheter with delirium in hospitalized patients and nursing home residents: an explorative analysis from the "Delirium Day 2015"

Backround: Use of indwelling urinary catheter (IUC) in older adults has negative consequences, including delirium. Aim: This analysis, from the "Delirium Day 2015", a nationwide multicenter prevalence study, aim to evaluate the association of IUC with delirium in hospitalized and Nursing Homes (NHs) patients. Methods: Patients underwent a comprehensive geriatric assessment, including the presence of IUC; inclusion criteria were age &gt; 65 years, being Italian speaker and providing informed consent; exclusion criteria were coma, aphasia, end-of-life status. Delirium was assessed using the 4AT test (score ≥ 4: possible delirium; scores 1-3: possible cognitive impairment). Results: Among 1867 hospitalized patients (mean age 82.0 ± 7.5 years, 58% female), 539 (28.9%) had IUC, 429 (22.9%) delirium and 675 (36.1%) cognitive impairment. IUC was significantly associated with cognitive impairment (OR 1.60, 95% CI 1.19-2.16) and delirium (2.45, 95% CI 1.73-3.47), this latter being significant also in the subset of patients without dementia (OR 2.28, 95% CI 1.52-3.43). Inattention and impaired alertness were also independently associated with IUC. Among 1454 NHs residents (mean age 84.4 ± 7.4 years, 70.% female), 63 (4.3%) had IUC, 535 (36.8%) a 4AT score ≥ 4, and 653 (44.9%) a 4AT score 1-3. The multivariate logistic regression analysis did not show a significant association between 4AT test or its specific items with IUC, neither in the subset of patients without dementia. Discussion: We confirmed a significant association between IUC and delirium in hospitalized patients but not in NHs residents. Conclusion: Environmental and clinical factors of acute setting might contribute to IUC-associated delirium occurrence

&quot;Delirium Day&quot;: A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys