Polynomial time algorithms for multicast network code construction

The famous max-flow min-cut theorem states that a source node s can send information through a network (V, E) to a sink node t at a rate determined by the min-cut separating s and t. Recently, it has been shown that this rate can also be achieved for multicasting to several sinks provided that the intermediate nodes are allowed to re-encode the information they receive. We demonstrate examples of networks where the achievable rates obtained by coding at intermediate nodes are arbitrarily larger than if coding is not allowed. We give deterministic polynomial time algorithms and even faster randomized algorithms for designing linear codes for directed acyclic graphs with edges of unit capacity. We extend these algorithms to integer capacities and to codes that are tolerant to edge failures

Differential Gene Expression-Based Connectivity Mapping Identified Novel Drug Candidate and Improved Temozolomide Efficacy for Glioblastoma

BACKGROUND: Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment. METHODS: We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM\u27s specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability. RESULTS: We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTEN CONCLUSION: PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC

MicroRNA-1 Attenuates the Growth and Metastasis of Small Cell Lung Cancer through CXCR4/FOXM1/RRM2 Axis

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS: A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS: Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis

Responding to COVID-19 : emerging practices in addiction medicine in 17 countries

Following the classification of the Coronavirus disease (COVID-19) as a pandemic by the World Health Organization (WHO), countries were encouraged to implement urgent and aggressive actions to change the course of the disease spread while also protecting the physical and mental health and well-being of all people. The challenges and solutions of providing prevention, treatment, and care for those affected with issues related to substance use and addictive behaviors are still being discussed by the global community. Several international documents have been developed for service providers and public health professionals working in the field of addiction medicine in the context of the pandemic (1–3), however, less is known about country-level responses. In the current paper we, as individual members of the Network of Early Career Professionals working in Addiction Medicine (NECPAM), discuss emerging country-level guidelines developed in the 6 months following the outbreak.The South African Medical Research Councilhttp://www.frontiersin.org/Psychiatryam2022Family Medicin

Predictors of Dropout from Outpatient Mental Health Services; A Study from Rohtak, India

Context: Dropout from mental health services is problematic in both developed and developing nations and often leads to poor outcomes. There is a lack of hospital-based studies assessing the factors responsible for treatment dropout from mental health services in Indian settings. This study aims to contribute in that direction by presenting a study done in a tertiary care hospital in North India. Methodology: This was a hospital-based retrospective chart review carried out on randomly selected 139 patients at a tertiary hospital from January 1, 2014, to June 30, 2014. For this chart review, an abstraction form was designed that recorded six sociodemographic variables, nine clinical factors, and two outcome variables (more than one follow-up and active follow-up till 6 months). Results: Out of 139 patients, 53 patients dropped out after the first visit and 105 patients dropped out by the end of 6 months. Lower education status (odds ratio [OR] = 8.2, 95% confidence interval [CI]: 2.30–29.50), severe mental illness (OR = 2.6, 95% CI: 1.05–6.49), and early referral to clinical psychologist (CP) (OR = 7.8, 95% CI: 1.87–6.49) were predictors of better rates of follow-up after first visit. Lower education status (OR = 4.9, 95% CI: 1.45–17.08), early referral to CP (OR = 5.8, 95% CI: 2.09–38.35), and previous treatment history (OR = 8.9, 95% CI: 1.97–17.52) were predictors of better rates of follow-up at the end of 6 months. Conclusion: The findings that education status, diagnosis, utilizing services of CP, and psychiatric services in past are correlated with dropout rates may be helpful in targeting patients who are more vulnerable to dropping out of care in the given setting

Large Scale Profiling of SARS-CoV-2-Infected Patients Identified Potential Therapeutic Host Targets and Drug Candidates for COVID-19

Given the rapid spread of SARS-CoV-2 and rising death toll of COVID-19 in the current absence of effective treatments, it is imperative that therapeutics are developed and made available to patients as quickly as possible. Publicly available COVID-19 patient data can be used to identify host therapeutic targets, tailoring treatments to the disease signatures observed in patients. In this study, we identify potential host therapeutic targets based on gene expression alterations observed in COVID-19 patients. We analyzed RNAseq data from airway samples of COVID-19 patients and healthy controls to detect significantly differentially expressed genes and pathways that present potential therapeutic targets. Our analysis revealed expression changes in key genes involved in activation of immune pathways, as well as genes targeted by SARS-CoV2 to interfere with normal host cell functioning. Critical changes were observed in a number of genes, including EIF2AK2, which was shown to play important roles in activating the interferon response and interfering with host cell translational machinery in SARS-CoV-2 infection, presenting a prospective therapeutic target. We also identified drugs with potential to modulate multiple therapeutic targets within the most significant pathways. Our results both validate key genes, pathways, and drug candidates that have been reported by other studies and suggest others that have not been well-characterized and warrant further investigation by future studies. Further investigation of these therapeutic targets and their drug interactions may lead to effective therapeutic strategies to combat the current COVID-19 pandemic and protect against future outbreaks.<br /