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Thousands of cancer surgeries were delayed during the peak of the COVID-19 pandemic. This study examines if surgical delays impact survival for breast, lung and colon cancers. PubMed/MEDLINE, EMBASE, Cochrane Library and Web of Science were searched. Articles evaluating the relationship between delays in surgery and overall survival (OS), disease-free survival (DFS) or cancer-specific survival (CSS) were included. Of the 14,422 articles screened, 25 were included in the review and 18 (totaling 2,533,355 patients) were pooled for meta-analyses. Delaying surgery for 12 weeks may decrease OS in breast (HR 1.46, 95%CI 1.28–1.65), lung (HR 1.04, 95%CI 1.02–1.06) and colon (HR 1.24, 95%CI 1.12–1.38) cancers. When breast cancers were analyzed by stage, OS was decreased in stages I (HR 1.27, 95%CI 1.16–1.40) and II (HR 1.13, 95%CI 1.02–1.24) but not in stage III (HR 1.20, 95%CI 0.94–1.53). Delaying breast, lung and colon cancer surgeries during the COVID-19 pandemic may decrease survival. •Delaying cancer surgeries during the COVID-19 pandemic may impact survival.•Surgical delays of 12 weeks decreases survival in breast, lung and colon cancers.•Surgical delays worsen survival in stage I and II breast cancers but not stage III.•Triage recommendations for future waves of COVID-19 should consider this evidence.

We recently identified a brief time period during postnatal development when the mammalian heart retains significant regenerative potential after amputation of the ventricular apex. However, one major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-d-old mice and found that this results in extensive myocardial necrosis and systolic dysfunction. Remarkably, the neonatal heart mounted a robust regenerative response, through proliferation of preexisting cardiomyocytes, resulting in full functional recovery within 21 d. Moreover, we show that the miR-15 family of microRNAs modulates neonatal heart regeneration through inhibition of postnatal cardiomyocyte proliferation. Finally, we demonstrate that inhibition of the miR-15 family from an early postnatal age until adulthood increases myocyte proliferation in the adult heart and improves left ventricular systolic function after adult MI. We conclude that the neonatal mammalian heart can regenerate after myocardial infarction through proliferation of preexisting cardiomyocytes and that the miR-15 family contributes to postnatal loss of cardiac regenerative capacity.

Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abnormal increases in intracellular Ca²⁺ during myocardial reperfusion can cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Therapeutic modulation of Ca²⁺ handling provides some cardioprotection against the paradoxical effects of restoring blood flow to the heart, highlighting the significance of Ca²⁺ overload to IR injury. Cardiac IR is also accompanied by dynamic changes in the expression of microRNAs (miRNAs); for example, miR-214 is upregulated during ischemic injury and heart failure, but its potential role in these processes is unknown. Here, we show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The cardioprotective roles of miR-214 during IR injury were attributed to repression of the mRNA encoding sodium/calcium exchanger 1 (Ncx1), a key regulator of Ca²⁺ influx; and to repression of several downstream effectors of Ca²⁺ signaling that mediate cell death. These findings reveal a pivotal role for miR-214 as a regulator of cardiomyocyte Ca²⁺ homeostasis and survival during cardiac injury.

Despite the major roles of choroid plexus epithelial cells (CPECs) in brain homeostasis and repair, their developmental lineage and diversity remain undefined. In simplified differentiations from human pluripotent stem cells, derived CPECs (dCPECs) display canonical properties and dynamic motile multiciliated phenotypes that interact with Aβ uptake. Single dCPEC transcriptomes over time correlate well with human organoid and fetal CPECs, while pseudotemporal and cell cycle analyses highlight the direct CPEC origin from neuroepithelial cells. In addition, time series analyses define metabolic (type 1) and ciliogenic dCPECs (type 2) at early timepoints, followed by type 1 diversification into anabolic-secretory (type 1a) and catabolic-absorptive subtypes (type 1b) as type 2 cells contract. These temporal patterns are then confirmed in independent derivations and mapped to prenatal stages using human tissues. In addition to defining the prenatal lineage of human CPECs, these findings suggest dynamic models of ChP support for the developing human brain. The choroid plexus is a crucial but understudied brain tissue. Here, the authors use stem cells and tissue samples to trace its origins and lineage during pregnancy and to create new models for its support of the developing human brain.

The perceptual quality of odors usually is robust to variability in concentration. However, maps of neural activation across the olfactory bulb glomerular layer are not stable in this respect; rather, glomerular odor representations both broaden and intensify as odorant concentrations are increased. The relative levels of activation among glomeruli, in contrast, remain relatively stable across concentrations, suggesting that the representation of odor quality may rely on these relational activity patterns. However, the neural normalization mechanisms enabling extraction of such relational representations are unclear. Using glomerular imaging activity profiles from the rat olfactory bulb together with computational modeling, we here show that (i) global normalization preserves concentration-independent odor-quality information; (ii) perceptual similarities, as assessed behaviorally, are better predicted by normalized than by raw bulbar activity profiles; and (iii) a recurrent excitatory circuit recently described in the olfactory bulb is capable of performing such normalization. We show that global feed-forward normalization in a sensory system is behaviorally relevant, and that a center-surround neural architecture does not necessarily imply center-surround function.

Employing wide-field optical imaging techniques supported by electrophysiological recordings, previous studies have demonstrated that stimulation of a spatially restricted area (point) in the sensory periphery results in a large evoked neuronal activity spread in mammalian primary cortices. In rats' primary cortices, such large evoked spreads extend diffusely in multiple directions, cross cortical cytoarchitectural borders and can trespass into other unimodal sensory areas. These point spreads are supported by a spatially matching, diffuse set of long-range horizontal projections within gray matter that extend in multiple directions and cross borders to interconnect different cortical areas. This horizontal projection system is in addition to well-known area-to-area clustered projections to defined targets through white matter. Could similar two-projection cortical systems also be found in cortical regions that differ in their cytoarchitectural structure? To address this question, an adeno-associated viral vector expressing green fluorescent protein (GFP) was injected as an anterograde tract tracer into granular somatosensory cortex (trunk area), dysgranular cortex (somatosensory dysgranular zone and extrastriate cortex) and agranular motor cortex (MCx). Irrespective of the injection site the same two projection systems were found, and their quantification revealed a close similarity to findings in primary sensory cortices. Following detailed reconstruction, the diffuse horizontal axon radiation was found to possess numerous varicosities and to include short, medium and long axons, the latter extending up to 5.2 mm. These \"proof of concept\" findings suggest that the similarity of the two projection systems among different cortical areas could potentially constitute a canonical motif of neocortical organization.

Neuroblastoma is the most common pediatric abdominal tumor and principally a p53 wild-type, highly vascular, aggressive tumor, with limited response to anti-VEGF therapies alone. MDM2 is a key inhibitor of p53 and a positive activator of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) activity with an important role in neuroblastoma pathogenesis. We hypothesized that concurrent inhibition of both MDM2 and VEGF signaling would have cooperative anti-tumor effects, potentiating anti-angiogenic strategies for neuroblastoma and other p53 wild-type tumors. We orthotopically implanted SH-SY5Y neuroblastoma cells into nude mice ( n  = 40) and treated as follows: control, bevacizumab, Nutlin-3a, combination of bevacizumab plus Nutlin-3a. Expression of HIF-1α and VEGF were measured by qPCR, Western blot, and ELISA. Tumor apoptosis was measured by immunohistochemistry and caspase assay. Angiogenesis was evaluated by immunohistochemistry for vascular markers (CD-31, type-IV collagen, αSMA). Both angiogenesis and metastatic burden were digitally quantified. In vitro, Nutlin-3a suppresses HIF-1α expression with subsequent downregulation of VEGF. Bevacizumab plus Nutlin-3a leads to significant suppression of tumor growth compared to control ( P  < 0.01) or either agent alone. Combination treated xenograft tumors display a marked decrease in endothelial cells ( P  < 0.0001), perivascular basement membrane ( P  < 0.04), and vascular mural cells ( P  < 0.004). Nutlin-3a alone and in combination with bevacizumab leads to significant tumor apoptosis ( P  < 0.0001 for both) and significant decrease in incidence of metastasis ( P  < 0.05) and metastatic burden ( P  < 0.03). Bevacizumab plus Nutlin-3a cooperatively inhibits tumor growth and angiogenesis in neuroblastoma in vivo with dramatic effects on tumor vascularity. Concomitantly targeting VEGF and p53 pathways potently suppresses tumor growth, and these results support further clinical development of this approach.

Background Choroid plexus epithelial cells express high levels of transthyretin, produce cerebrospinal fluid and many of its proteins, and make up the blood-cerebrospinal fluid barrier. Choroid plexus epithelial cells are vital to brain health and may be involved in neurological diseases. Transgenic mice containing fluorescent and luminescent reporters of these cells would facilitate their study in health and disease, but prior transgenic reporters lost expression over the early postnatal period. Methods Human bacterial artificial chromosomes in which the transthyretin coding sequence was replaced with DNA for tdTomato or luciferase 2 were used in pronuclear injections to produce transgenic mice. These mice were characterized by visualizing red fluorescence, immunostaining, real-time reverse transcription polymerase chain reaction, and luciferase enzyme assay. Results Reporters were faithfully expressed in cells that express transthyretin constitutively, including choroid plexus epithelial cells, retinal pigment epithelium, pancreatic islets, and liver. Expression of tdTomato in choroid plexus began at the appropriate embryonic age, being detectable by E11.5. Relative levels of tdTomato transcript in the liver and choroid plexus paralleled relative levels of transcripts for transthyretin. Expression remained robust over the first postnatal year, although choroid plexus transcripts of tdTomato declined slightly with age whereas transthyretin remained constant. TdTomato expression patterns were consistent across three founder lines, displayed no sex differences, and were stable across several generations. Two of the tdTomato lines were bred to homozygosity, and homozygous mice are healthy and fertile. The usefulness of tdTomato reporters in visualizing and analyzing live Transwell cultures was demonstrated. Luciferase activity was very high in homogenates of choroid plexus and continued to be expressed through adulthood. Luciferase also was detectable in eye and pancreas. Conclusions Transgenic mice bearing fluorescent and luminescent reporters of transthyretin should prove useful for tracking transplanted choroid plexus epithelial cells, for purifying the cells, and for reporting their derivation from stem cells. They also should prove useful for studying transthyretin synthesis by other cell types, as transthyretin has been implicated in many functions and conditions, including clearance of β-amyloid peptides associated with Alzheimer’s disease, heat shock in neurons, processing of neuropeptides, nerve regeneration, astrocyte metabolism, and transthyretin amyloidosis.

Objectives Solid renal masses have unknown malignant potential with commonly utilized imaging. Biopsy can offer a diagnosis of cancer but has a high non-diagnostic rate and complications. Reported use of multiparametric magnetic resonance imaging (mpMRI) to diagnose aggressive histology (i.e., clear cell renal cell carcinoma (ccRCC)) via a clear cell likelihood score (ccLS) was based on retrospective review of cT1a tumors. We aim to retrospectively assess the diagnostic performance of ccLS prospectively assigned to renal masses of all stages evaluated with mpMRI prior to histopathologic evaluation. Methods In this retrospective cohort study from June 2016 to November 2019, 434 patients with 454 renal masses from 2 institutions with heterogenous patient populations underwent mpMRI with prospective ccLS assignment and had pathologic diagnosis. ccLS performance was assessed by contingency table analysis. The association between ccLS and ccRCC was assessed with logistic regression. Results Mean age and tumor size were 60 ± 13 years and 5.4 ± 3.8 cm. Characteristics were similar between institutions except for patient age and race (both p  < 0.001) and lesion laterality and histology (both p  = 0.04). The PPV of ccLS increased with each increment in ccLS (ccLS1 5% [3/55], ccLS2 6% [3/47], ccLS3 35% [20/57], ccLS4 78% [85/109], ccLS5 93% [173/186]). Pooled analysis for ccRCC diagnosis revealed sensitivity 91% (258/284), PPV 87% (258/295) for ccLS ≥ 4, and specificity 56% (96/170), NPV 94% (96/102) for ccLS ≤ 2. Diagnostic performance was similar between institutions. Conclusions We confirm the optimal diagnostic performance of mpMRI to identify ccRCC in all clinical stages. High PPV and NPV of ccLS can help inform clinical management decision-making. Key Points • The positive predictive value of the clear cell likelihood score (ccLS) for detecting clear cell renal cell carcinoma was 5% (ccLS1), 6% (ccLS2), 35% (ccLS3), 78% (ccLS4), and 93% (ccLS5). Sensitivity of ccLS ≥ 4 and specificity of ccLS ≤ 2 were 91% and 56%, respectively. • When controlling for confounding variables, ccLS is an independent risk factor for identifying clear cell renal cell carcinoma. • Utilization of the ccLS can help guide clinical care, including the decision for renal mass biopsy, reducing the morbidity and risk to patients.

There are approximately 300 million cases of malaria each year, resulting in 1 million deaths worldwide. Family physicians often encounter patients preparing to travel to malaria-endemic regions. Physicians should have basic knowledge of parasite transmission and malaria prevention. The risk of malaria acquisition is based largely on geographic location and travel season. Most cases occur in sub-Saharan Africa, the Indian subcontinent, and Southeast Asia between the months of May and December. Key elements in prevention include barrier protection and chemoprophylaxis. Travelers to malaria-endemic areas should be advised to use mosquito repellent at all times and bed netting at night. Prophylactic medication should be initiated before travel and continued after return. Travelers should be warned that malaria symptoms can present up to one year after a mosquito bite. Symptoms are vague, and may include fever, chills, arthralgias, and headaches. Travelers experiencing symptoms should seek prompt medical attention.