COVID-19 impact on firm investment-Evidence from Chinese publicly listed firms.

The COVID-19 outbreak had a significant impact on business cash flows and investment activities. This paper examined the COVID-19 impact on Chinese business investment in 3326 A-share listed quarterly financial reports, from which it was found that the negative relationship was more pronounced in the large, eastern Chinese state-owned firms. Using a propensity score matching method and difference-in-differences estimation, corporate financial flexibility was also examined, with the results indicating that high cash flexibility provided a buffer that allowed firms to better deal with adverse external shocks as the firms that had high cash flexibility were able to significantly increase their investments after the COVID-19 outbreak. Various robustness tests were conducted, all of which verified the robustness of the results. Overall, the empirical results provided evidence that the COVID-19 pandemic in China had a negative impact on Chinese listed firms, and verified the vital role of flexible financial reserves for firm survival and development during crises.

A new correlation clustering method for cancer mutation analysis.

MOTIVATION: Cancer genomes exhibit a large number of different alterations that affect many genes in a diverse manner. An improved understanding of the generative mechanisms behind the mutation rules and their influence on gene community behavior is of great importance for the study of cancer. RESULTS: To expand our capability to analyze combinatorial patterns of cancer alterations, we developed a rigorous methodology for cancer mutation pattern discovery based on a new, constrained form of correlation clustering. Our new algorithm, named C3 (Cancer Correlation Clustering), leverages mutual exclusivity of mutations, patient coverage and driver network concentration principles. To test C3, we performed a detailed analysis on TCGA breast cancer and glioblastoma data and showed that our algorithm outperforms the state-of-the-art CoMEt method in terms of discovering mutually exclusive gene modules and identifying biologically relevant driver genes. The proposed agnostic clustering method represents a unique tool for efficient and reliable identification of mutation patterns and driver pathways in large-scale cancer genomics studies, and it may also be used for other clustering problems on biological graphs. AVAILABILITY AND IMPLEMENTATION: The source code for the C3 method can be found at https://github.com/jackhou2/C3 CONTACTS: jianma@cs.cmu.edu or milenkov@illinois.eduSupplementary information: Supplementary data are available at Bioinformatics online.

Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

A network-assisted co-clustering algorithm to discover cancer subtypes based on gene expression.

BACKGROUND: Cancer subtype information is critically important for understanding tumor heterogeneity. Existing methods to identify cancer subtypes have primarily focused on utilizing generic clustering algorithms (such as hierarchical clustering) to identify subtypes based on gene expression data. The network-level interaction among genes, which is key to understanding the molecular perturbations in cancer, has been rarely considered during the clustering process. The motivation of our work is to develop a method that effectively incorporates molecular interaction networks into the clustering process to improve cancer subtype identification. RESULTS: We have developed a new clustering algorithm for cancer subtype identification, called "network-assisted co-clustering for the identification of cancer subtypes" (NCIS). NCIS combines gene network information to simultaneously group samples and genes into biologically meaningful clusters. Prior to clustering, we assign weights to genes based on their impact in the network. Then a new weighted co-clustering algorithm based on a semi-nonnegative matrix tri-factorization is applied. We evaluated the effectiveness of NCIS on simulated datasets as well as large-scale Breast Cancer and Glioblastoma Multiforme patient samples from The Cancer Genome Atlas (TCGA) project. NCIS was shown to better separate the patient samples into clinically distinct subtypes and achieve higher accuracy on the simulated datasets to tolerate noise, as compared to consensus hierarchical clustering. CONCLUSIONS: The weighted co-clustering approach in NCIS provides a unique solution to incorporate gene network information into the clustering process. Our tool will be useful to comprehensively identify cancer subtypes that would otherwise be obscured by cancer heterogeneity, using high-throughput and high-dimensional gene expression data.

Outcome of transvaginal mesh and tape removed for pain only.

PURPOSE: Because there is reluctance to operate for pain, we evaluated midterm outcomes of vaginal mesh and synthetic suburethral tape removed for pain as the only indication. MATERIALS AND METHODS: After receiving institutional review board approval we reviewed a prospective database of women without a neurogenic condition who underwent surgery for vaginal mesh or suburethral tape removal with a focus on pain as the single reason for removal and a minimum 6-month followup. The primary outcome was pain level assessed by a visual analog scale (range 0 to 10) at baseline and at each subsequent visit with the score at the last visit used for analysis. Parameters evaluated included demographics, mean time to presentation and type of mesh or tape inserted. RESULTS: From 2005 to 2013, 123 patients underwent surgical removal of mesh (69) and suburethral tape (54) with pain as the only indication. Mean followup was 35 months (range 6 to 59) in the tape group and 22 months (range 6 to 47) in the mesh group. The visual analog scale score decreased from a mean preoperative level of 7.9 to 0.9 postoperatively (p = 0.0014) in the mesh group and from 5.3 to 1.5 (p = 0.00074) in the tape group. Pain-free status, considered a score of 0, was achieved in 81% of tape and 67% of mesh cases, respectively. No statistically significant difference was found between the groups. CONCLUSIONS: When pain is the only indication for suburethral tape or vaginal mesh removal, a significant decrease in the pain score can be durably expected after removal in most patients at midterm followup.

The role of fascial slings in the treatment of stress urinary incontinence in women: a 2013 update.

During the last decade, a variety of commercial innovations in synthetic sling materials have emerged as a result of an evolution in the understanding of the pathophysiology of stress urinary incontinence (SUI), and a push to less invasive surgical approaches. The advent of midurethral slings (MUS), with their relative ease of placement, has modernized and become the most commonly used technique for treatment of SUI. Nevertheless, this innovative technology has been associated with complications not previously associated with anti-incontinence procedures. In this article, we review the current literature regarding the use, indications, and efficacy of pubovaginal fascial slings (PVS) in the era of expanding synthetic sling use.

Peritumoral brain edema in intracranial meningiomas: the emergence of vascular endothelial growth factor-directed therapy.

Meningioma is the second most common type of adult intracranial neoplasm. A substantial subset of patients present with peritumoral brain edema (PTBE), which can cause significant morbidity via mass effect, complicate surgical management, and impact the safety of stereotactic radiosurgery. Recent studies suggest a close relationship between vascular endothelial growth factor-A (VEGF-A) expression and PTBE development in meningiomas. The authors performed a systematic review of the literature on the pathogenesis of PTBE in meningiomas, the effectiveness of steroid therapy, the role played by VEGF-A, and the current clinical evidence for antiangiogenic therapy to treat peritumoral brain edema. Mounting evidence suggests VEGF-A is secreted directly by meningioma cells to induce angiogenesis and edemagenesis of tumoral as well as peritumoral brain tissue. The VEGF-A cascade results in recruitment of cerebral-pial vessels and disruption of the tumor-brain barrier, which appear to be requisite for VEGF-A to have an edemagenic effect. Results of preliminary clinical studies suggest VEGF-directed therapy has modest activity against recurrent and progressive meningioma growth but can alleviate PTBE in some patients. A comprehensive understanding of the VEGF-A pathway and its modulators may hold the key to an effective therapeutic approach to treating PTBE associated with meningiomas. Further clinical trials with larger patient cohorts and longer follow-up periods are warranted to confirm the efficacy of VEGF-directed therapy.

Transition of research focus from vasospasm to early brain injury after subarachnoid hemorrhage.

Subarachnoid hemorrhage is a devastating disease that can be difficult to manage. Not only is the initial bleeding and rebleeding associated with high mortality, but a large fraction of patients also develop a delayed neurological deficit even when the aneurysm was successfully secured with clipping or coiling. Past research effort has traditionally been focused on vasospasm, which was conceived to be the sole factor for delayed neurological deficit. The failure of anti-vasospastic drugs to improve outcome in clinical trials has brought into focus the significance of early brain injury. The immediate events associated with subarachnoid hemorrhage, including increased intracranial pressure, decreased cerebral blood flow and global ischemia initiate a cascade of pathological changes that occur before the onset of delayed vasospasm. These pathological changes in the very early stage of the hemorrhage propagate and cause blood-brain barrier disruption, inflammation, oxidative stress and cell death. Focusing only on the treatment of vasospasm with complete disregard for early brain injury is insufficient for the management of subarachnoid hemorrhage. Instead, a therapeutic intervention has to aim at stopping the molecular cascades of early brain injury that may lead to long-term deficits in addition to vasospasm. We review the pathological mechanisms of early brain injury, which may reveal new therapeutic avenues that can be exploited to serve as combination therapy with anti-vasospasm medications in the future.

Advanced maternal age as a risk factor for stress urinary incontinence: a review of the literature.

The pathophysiology of stress urinary incontinence (SUI) is multifactorial and evidence supports a critical role of pregnancy and vaginal delivery. This review dissects epidemiologic literature to determine the weight of evidence on the role of advanced maternal age (AMA) as a risk factor for the development of subsequent or persistent SUI. We conducted a Medline search using the keywords postpartum, SUI, maternal age, pregnancy, and incontinence. The published literature was critically analyzed. Evidence supports that childbirth trauma contributes to the development and severity of SUI. Yet, there is contradicting evidence as to whether AMA increases the risk. AMA clearly represents an independent risk factor for postpartum SUI. However, long-term studies did not confirm this observation. Whether this finding is suggestive of a true biologic signal that is lost with competing risk factors over time warrants further research.

A sweet potato gene index established by de novo assembly of pyrosequencing and Sanger sequences and mining for gene-based microsatellite markers.

BACKGROUND: Sweetpotato (Ipomoea batatas (L.) Lam.), a hexaploid outcrossing crop, is an important staple and food security crop in developing countries in Africa and Asia. The availability of genomic resources for sweetpotato is in striking contrast to its importance for human nutrition. Previously existing sequence data were restricted to around 22,000 expressed sequence tag (EST) sequences and ~ 1,500 GenBank sequences. We have used 454 pyrosequencing to augment the available gene sequence information to enhance functional genomics and marker design for this plant species. RESULTS: Two quarter 454 pyrosequencing runs used two normalized cDNA collections from stems and leaves from drought-stressed sweetpotato clone Tanzania and yielded 524,209 reads, which were assembled together with 22,094 publically available expressed sequence tags into 31,685 sets of overlapping DNA segments and 34,733 unassembled sequences. Blastx comparisons with the UniRef100 database allowed annotation of 23,957 contigs and 15,342 singletons resulting in 24,657 putatively unique genes. Further, 27,119 sequences had no match to protein sequences of UniRef100database. On the basis of this gene index, we have identified 1,661 gene-based microsatellite sequences, of which 223 were selected for testing and 195 were successfully amplified in a test panel of 6 hexaploid (I. batatas) and 2 diploid (I. trifida) accessions. CONCLUSIONS: The sweetpotato gene index is a useful source for functionally annotated sweetpotato gene sequences that contains three times more gene sequence information for sweetpotato than previous EST assemblies. A searchable version of the gene index, including a blastn function, is available at http://www.cipotato.org/sweetpotato_gene_index.

DawnRank: discovering personalized driver genes in cancer.

Large-scale cancer genomic studies have revealed that the genetic heterogeneity of the same type of cancer is greater than previously thought. A key question in cancer genomics is the identification of driver genes. Although existing methods have identified many common drivers, it remains challenging to predict personalized drivers to assess rare and even patient-specific mutations. We developed a new algorithm called DawnRank to directly prioritize altered genes on a single patient level. Applications to TCGA datasets demonstrated the effectiveness of our method. We believe DawnRank complements existing driver identification methods and will help us discover personalized causal mutations that would otherwise be obscured by tumor heterogeneity. Source code can be accessed at http://bioen-compbio.bioen.illinois.edu/DawnRank/.

Successful resection of anterior and anterolateral lesions at the craniovertebral junction using a simple posterolateral approach.

Tumors at the craniovertebral junction (CVJ) often present a challenge due to proximity to vital neurovascular structures. In the last few decades, many authors have proposed complex surgical approaches to access pathologies located anterior or anterolateral to the CVJ with the hopes of reducing morbidity. We propose that the simple posterolateral approach in a semi-sitting position can be used to resect most anterior and anterolateral CVJ tumors safely and effectively. We retrospectively reviewed the clinical series of 10 patients treated by the senior author using the posterolateral suboccipital approach to treat anterior or anterolateral CVJ pathologies. We describe our surgical techniques, outcomes, and present illustrative patients. Gross total resection was achieved in eight patients (80%). Good functional outcome (Glasgow Outcome Scale 4-5) was obtained in all patients. Preoperative symptoms and deficits were improved (78%) or stable (22%) in all patients. There was one (10%) surgical complication that was cerebrospinal fluid leak requiring reoperation. There was no permanent morbidity or mortality in this series. There were two (20%) medical complications including deep vein thrombosis and pulmonary embolus. There were three (30%) transient neurologic complications, dysphagia in two and dysarthria in one, all of which resolved completely in early follow-up. The majority of anterior or anterolateral CVJ lesions can be successfully removed using the simple posterolateral approach.

Remote post-conditioning reduces hypoxic damage early after experimental stroke.

OBJECTIVES: Given that reliable markers for early ischemic brain damage are lacking, we set out to test whether pimonidazole can be used as a reliable tool in the quantification of hypoxic insults, at early time points following experimental stroke. METHODS: We have used semi-quantitative Western blotting detection of pimonidazole adducts in a rat model of reversible middle cerebral artery occlusion (MCAO), treated with remote post-conditioning. RESULTS: First, we demonstrated that a linear relationship exist between pimonidazole binding in the ischemic hemisphere and duration of ischemia, in animals subjected to 5, 15, 30, or 60 minutes of occlusion followed by 120 minutes of reflow. Then we showed a significant reduction in pimonidazole binding in the infarcted hemisphere, when rats with 60 minutes of MCAO, immediately after establishment of cerebral reflow, had 3×15 minutes intermittent hind limb ischemia followed by 24-hour survival. We analysed the middle cerebral arteries from animals with 60 minutes of MCAO and early remote post-conditioning, followed by 30 minutes, 24, or 48 hours of reflow. At 24 hours of reflow increases in phosphorylated protein kinase C-alpha with concomitantly increased levels of p38 phosphorylation were observed. CONCLUSIONS: Our investigation demonstrates that pimonidazole can be used for quantifying ischemic impact in stroke, even after very short survival times. It furthermore shows that early remote post-conditioning reduces ischemic damage, probably through hyperpolarization and reduced reflow vasospasm in the conduit middle cerebral arteries.

Age-related degeneration of corpus callosum in the 90+ years measured with stereology.

The present study is aimed to assess age-related structural changes in corpus callosum with stereology in 21 postmortem human brains without neuropathology, of age 65-75 (Group A, n = 7), 80-85 (Group B, n = 7), and 94-105 (Group C, n = 7) years. Cross-sectional area, fiber number and density decrease in Group B compared with Group A, then remain unchanged in Group C. Mean fiber diameter increases with age. Cross-sectional area shows strong positive correlation to fiber numbers and negative correlation to mean fiber thickness. With age, modest but significant change in fiber size including a decrease in the percentage of 1-2-µm fibers and an increase in 2-3-µm fibers was observed. Fiber density shows a steeper decline with age in the anterior compared with posterior segments. Neurodegeneration is an ongoing process where the anterior corpus callosum is more susceptible to age-related degeneration. Corpus callosum cross-sectional area atrophy is mostly related to decline in fiber number and density rather than demyelination, with preferential disruption of small caliber fibers.

Metastasis to the penis from rectal adenocarcinoma.

Penile cancer is a serious but largely under-represented phenomenon in many of the large national cancer databases. Even more rare is the presentation of solitary metastasis to the penis from a gastrointestinal primary site. This case describes one such case of metastasis of rectal adenocarcinoma and details the patient's treatment modalities. Ultimately, although the precise etiology of this particular manifestation is not well understood, the prognosis is poor in the small group that it affects. No individual treatment has been proven superior with regard to long term survival.

Application of immunohistochemistry in stereology for quantitative assessment of neural cell populations illustrated in the Göttingen minipig.

BACKGROUND: Stereology is the study of estimating geometric quantities. When successfully applied, the combination of immunohistochemistry (IHC) and stereology eliminates intra- and interobserver variability for cell type identification. METHODOLOGY/PRINCIPAL FINDINGS: We propose a method to validate existing antibody based cell type markers for stereological application. Comparison was made on the 100-days-old Göttingen minipig (G-mini) neocortex between estimates of total neuron number derived from Giemsa staining using morphological criteria and immunohistochemistry-based cell counting with NeuN. The mean total neuron numbers estimated by the two staining methods were not significantly different. Estimated quantities, including glial cell number, neocortical volume, cell densities and glial-to-neuron ratio were also presented. Additionally, we assessed other commonly used glial markers and discussed how to evaluate the advantages and disadvantages of these markers for stereological estimation of cell number. CONCLUSION/SIGNIFICANCE: The concordance in quantitative estimates of total neuron number derived from NeuN- and Giemsa-stained sections provides evidence for the sensitivity and specificity of NeuN as a neuronal marker in the G-mini. Although time-consuming, quantitative validation of IHC should always be considered in stereological studies if there is doubt of the sensitivity, specificity, or reproducibility of cell type markers. Inaccurate staining may cause both over- and underestimation of the total cell number and inflict considerable limitation when analyzing the results.

The importance of early brain injury after subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency that accounts for 5% of all stroke cases. Individuals affected are typically in the prime of their lives (mean age 50 years). Approximately 12% of patients die before receiving medical attention, 33% within 48 h and 50% within 30 days of aSAH. Of the survivors 50% suffer from permanent disability with an estimated lifetime cost more than double that of an ischemic stroke. Traditionally, spasm that develops in large cerebral arteries 3-7 days after aneurysm rupture is considered the most important determinant of brain injury and outcome after aSAH. However, recent studies show that prevention of delayed vasospasm does not improve outcome in aSAH patients. This finding has finally brought in focus the influence of early brain injury on outcome of aSAH. A substantial amount of evidence indicates that brain injury begins at the aneurysm rupture, evolves with time and plays an important role in patients' outcome. In this manuscript we review early brain injury after aSAH. Due to the early nature, most of the information on this injury comes from animals and few only from autopsy of patients who died within days after aSAH. Consequently, we began with a review of animal models of early brain injury, next we review the mechanisms of brain injury according to the sequence of their temporal appearance and finally we discuss the failure of clinical translation of therapies successful in animal models of aSAH.

Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage.

The inflammatory response plays a pivotal role in propagating injury of intracerebral hemorrhage (ICH). Glucagon-like-peptide-1 (GLP-1) is a hormone with antidiabetic effect and may also have antiinflammatory properties. Despite consensus that the glucoregulatory action is mediated by the GLP-1 receptor (GLP-1R), mechanisms in the brain remain unclear. We investigated the effect of a long-acting GLP-1 analog, liraglutide, and its truncated metabolite, GLP-1(9-36)a from dipeptidyl peptidase-4 (DPP-4) cleavage in ICH-induced brain injury. Primary outcomes were cerebral edema formation, neurobehavior, and inflammatory parameters. GLP-1(9-36)a, GLP-1R inhibitor, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation inhibitor and DPP-4 inhibitor were administered to examine the mechanisms of action. Liraglutide suppressed neuroinflammation, prevented brain edema and neurologic deficit following ICH, which were partially reversed by GLP-1R inhibitor and AMPK phosphorylation inhibitor. Liraglutide-mediated AMPK phosphorylation was unaffected by GLP-1R inhibitor, and was found to be induced by GLP-1(9-36)a. GLP-1(9-36)a showed salutary effects on primary outcomes that were reversed by AMPK phosphorylation inhibitor but not by GLP-1R inhibitor. Liraglutide and DPP-4 inhibitor co-administration reversed liraglutide-mediated AMPK phosphorylation and antiinflammatory effects. Liraglutide exerted duals actions and the antiinflammatory effects are partially mediated by its metabolite in a phosphorylated AMPK-dependent manner. Therapies that inhibit GLP-1 degradation may weaken the metabolite-mediated effects.

Phencyclidine treatment increases NR2A and NR2B N-methyl-D-aspartate receptor subunit expression in rats.

Administration of noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine to rats on postnatal days 7, 9, and 11 induces apoptosis in prefrontal cortex and hippocampus. In adulthood, these animals display cognitive impairment of working memory, reversal learning and attention that are similar to clinical observations in schizophrenia. In this study, expression of different NMDAR subunits, the postsynaptic mGlu5 receptor and the connecting NMDAR-mGluR5 intracellular postsynaptic density proteins have been measured in adult rats after treatment with phencyclidine on postnatal days 7, 9, and 11. We found that these animals exhibited elevated expression in medial prefrontal cortex of the NR2A and NR2B NMDA receptor subunits in adulthood. These results indicate how behavioral changes in a developmental model for cognitive dysfunction involve changes to specific molecular subsets of the cortical glutamate system.