A fast look-up method for Bayesian mean-parameterised Conway-Maxwell-Poisson regression models.

Count data that are subject to both under and overdispersion at some hierarchical level cannot be readily accommodated by classic models such as Poisson or negative binomial regression models. The mean-parameterised Conway-Maxwell-Poisson distribution allows for both types of dispersion within the same model, but is doubly intractable with an embedded normalising constant. We propose a look-up method where pre-computing values of the rate parameter dramatically reduces computing times and renders the proposed model a practicable alternative when faced with such bidispersed data.

Cost Analysis of Buprenorphine Extended-Release Injection Versus Sublingual Buprenorphine/Naloxone Tablets in a Correctional Setting.

Incarcerated clients experience high rates of opioid use disorder and overdose. It is critical that opioid agonist treatment (OAT) is provided in correctional facilities. However, few receive OAT due to concerns about diversion, misuse, and safety.

Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer.

CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage.

Incidence risk of peripheral edema in cancer patients treated with PD-1/PD-L1 inhibitors: A PRISMA guideline systematic review and meta-analysis.

Purpose: To elucidate the relationship between peripheral edema and programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors, the meta-analysis was performed.

Method: Following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses, all-grade and grade 3-5 of peripheral edema data extracted from clinical trials were taken into account for the final comprehensive assessments.

Results: Twenty-seven PD-1/PD-L1-related clinical trials with peripheral edema data were collected.

VRK1 Is a Synthetic-Lethal Target in VRK2-Deficient Glioblastoma.

Unlabelled: Synthetic lethality is a genetic interaction that results in cell death when two genetic deficiencies co-occur but not when either deficiency occurs alone, which can be co-opted for cancer therapeutics. Pairs of paralog genes are among the most straightforward potential synthetic-lethal interactions by virtue of their redundant functions. Here, we demonstrate a paralog-based synthetic lethality by targeting vaccinia-related kinase 1 (VRK1) in glioblastoma (GBM) deficient of VRK2, which is silenced by promoter methylation in approximately two thirds of GBM.

The Significance of Tumor Microenvironment Score for Breast Cancer Patients.

Purpose: This study was designed to clarify the prognostic value of tumor microenvironment score and abnormal genomic alterations in TME for breast cancer patients.

Method: The TCGA-BRCA data were downloaded from TCGA and analyzed with R software. The results from analyses were further validated using the dataset from GSE96058, GSE124647, and GSE25066.

A novel classification method for NSCLC based on the background interaction network and the edge-perturbation matrix.

The biological functional network of tumor tissues is relatively stable for a period of time and under different conditions, so the impact of tumor heterogeneity is effectively avoided. Based on edge perturbation, functional gene interaction networks were used to reveal the pathological environment of patients with non-small cell carcinoma at the individual level, and to identify cancer subtypes with the same or similar status, and then a multi-dimensional and multi-omics comprehensive analysis was put into practice. Two edge perturbation subtypes were identified through the construction of the background interaction network and the edge-perturbation matrix (EPM).

Significance of CD8 T cell infiltration-related biomarkers and the corresponding prediction model for the prognosis of kidney renal clear cell carcinoma.

Cytotoxic T cells expressing cell surface CD8 played a key role in anti-cancer immunotherapy, including kidney renal clear cell carcinoma (KIRC). Here we set out to comprehensively analyze and evaluate the significance of CD8 T cell-related markers for patients with KIRC. We checked immune cell response in KIRC and identified cell type-specific markers and related pathways in the tumor-infiltrating CD8 T (TIL-CD8T) cells.

Dynamic reconfiguration of pro-apoptotic BAK on membranes.

BAK and BAX, the effectors of intrinsic apoptosis, each undergo major reconfiguration to an activated conformer that self-associates to damage mitochondria and cause cell death. However, the dynamic structural mechanisms of this reconfiguration in the presence of a membrane have yet to be fully elucidated. To explore the metamorphosis of membrane-bound BAK, we employed hydrogen-deuterium exchange mass spectrometry (HDX-MS).

Assessment of the Clinical Trials Safety Profile of PD-1/PD-L1 Inhibitors Among Patients With Cancer: An Updated Systematic Review and Meta-Analysis.

Background: Understanding the safety and adverse event profiles of PD-1/PD-L1 inhibitors is important in guiding cancer immunotherapy. Consequently, we designed this meta-analysis to evaluate the safety of PD-1/PD-L1 inhibitors in clinical trials involving cancer patients.

Methods: Four safety indicators comprising treatment-related adverse events, death, discontinuation of therapy and grades 3-5 adverse events were evaluated using the random effect model.

Clinical Performance of the Point-of-Care cobas Liat for Detection of SARS-CoV-2 in 20 Minutes: a Multicenter Study.

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.

FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression.

Optimization of AsCas12a for combinatorial genetic screens in human cells.

Cas12a RNA-guided endonucleases are promising tools for multiplexed genetic perturbations because they can process multiple guide RNAs expressed as a single transcript, and subsequently cleave target DNA. However, their widespread adoption has lagged behind Cas9-based strategies due to low activity and the lack of a well-validated pooled screening toolkit. In the present study, we describe the optimization of enhanced Cas12a from Acidaminococcus (enAsCas12a) for pooled, combinatorial genetic screens in human cells.

Synthetic lethality as an engine for cancer drug target discovery.

The first wave of genetically targeted therapies for cancer focused on drugging gene products that are recurrently mutated in specific cancer types. However, mutational analysis of tumours has largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches. Furthermore, some known genetic drivers of cancer have not been directly targeted yet owing to their molecular structure (undruggable oncogenes) or because they result in functional loss (tumour suppressor genes).

CD56 CD16 Natural Killer Cell Profiling in Melanoma Patients Receiving a Cancer Vaccine and Interferon-α.

Natural killer (NK) cells are innate cytotoxic and immunoregulatory lymphocytes that have a central role in anti-tumor immunity and play a critical role in mediating cellular immunity in advanced cancer immunotherapies, such as dendritic cell (DC) vaccines. Our group recently tested a novel recombinant adenovirus-transduced autologous DC-based vaccine that simultaneously induces T cell responses against three melanoma-associated antigens for advanced melanoma patients. Here, we examine the impact of this vaccine as well as the subsequent systemic delivery of high-dose interferon-α2b (HDI) on the circulatory NK cell profile in melanoma patients.

Capmatinib (INC280) Is Active Against Models of Non-Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation.

Purpose: The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and in combination. Here, we describe the preclinical data of capmatinib, which supported the clinical biomarker strategy for rational patient selection.

Experimental Design: The selectivity and cellular activity of capmatinib were assessed in large cellular screening panels.

Infigratinib Mediates Vascular Normalization, Impairs Metastasis, and Improves Chemotherapy in Hepatocellular Carcinoma.

The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGF receptor (FGFR) expression in 17.7% (11 of 62) of hepatocellular carcinoma (HCC) models.

Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor-Positive Advanced Breast Cancer: A Phase 1b Clinical Trial.

Importance: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in patients with estrogen receptor-positive (ER+), endocrine therapy-resistant breast cancers.

Objective: To assess the maximum tolerated dose (MTD), safety, and activity of alpelisib, an oral, PI3Kα-specific inhibitor, plus fulvestrant in patients with ER+ advanced breast cancer (ABC).

Design, Setting, And Participants: An open-label, single-arm, phase 1b study of alpelisib plus fulvestrant was conducted at 10 centers in 5 countries.

Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody.

Background: Aberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive.

Methods: With the goal to investigate the molecular basis of MET amplification (MET) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring MET (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo.

Let's Talk About B: Barriers to Hepatitis B Screening and Vaccination Among Asian and South Asian Immigrants in British Columbia.

Introduction: Chronic hepatitis B (HBV) is prevalent among Asian immigrants in Canada with high morbidity and mortality rates. While some studies have identified barriers to health care and information access, few have studied the impact of culturally relevant information and addressed challenges with recommendations for effective public education and outreach programs.

Methods: Culturally tailored HBV education workshops were delivered over a 12-month period to Chinese, Filipino, Korean and Punjabi immigrants in Lower Mainland, British Columbia (BC).

Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study.

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule.

Genomic Analysis of Nasopharyngeal Carcinoma Reveals TME-Based Subtypes.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer characterized by a poor prognosis and a high level of lymphocyte infiltrate. Genetic hallmarks of NPC are not completely known but include deletion of the p16 () locus and mutations in NF-κB pathway components, with a relatively low total mutational load. To better understand the genetic landscape, an integrated genomic analysis was performed using a large clinical cohort of treatment-naïve NPC tumor specimens.