Severe febrile neutropenia and pancytopenia in a patient with advanced hepatocellular carcinoma treated with atezolizumab and bevacizumab: a case report.

Background: Immune checkpoint inhibitors (ICIs), agents that stimulate T-cell function, have become the standard first-line treatment for unresectable hepatocellular carcinoma (HCC). However, they may also cause immune-related adverse events (irAEs), which are rare and have not been extensively reported. Here, we describe a case of severe febrile neutropenia and pancytopenia after atezolizumab plus bevacizumab (atezo/bev) therapy and its treatment course. Case Description: The combination of atezo/bev was initiated as the first-line treatment for a man in his early 50s, who was diagnosed with unresectable HCC. The first treatment cycle was administered in the outpatient setting, and the patient developed a fever of 39.0 ℃ 10 days after therapy initiation. He presented 5 days later with persistent fever as well as a headache, vomiting, chills, generalized pain, fatigue, mild abdominal discomfort, and a burning rash present on his neck and face. Complete blood counts showed severe neutropenia [absolute neutrophil count (ANC) of 90 cells/µL], leukopenia [white blood cell (WBC) count 500 cells/µL], thrombocytopenia [platelet count (PC) 18,000 cells/µL], and mild anemia (hemoglobin level 12.6 gm/dL). Imaging findings showed colitis on computed tomography (CT). Atezo/bev therapy was discontinued. Treatment plan constituted of cefepime and filgrastim, a recombinant form of the naturally occurring granulocyte colony-stimulating factor (G-CSF) for febrile neutropenia, metronidazole for colitis, and intravenous methylprednisolone for immune-related toxicities. The patient fully recovered after 4 days of admission. Conclusions: In conclusion, we observed temporary severe febrile neutropenia and pancytopenia during systemic immunotherapy in a patient with unresectable HCC. Healthcare providers should consider hematological irAEs (hem-irAEs) in patients after the administration of ICIs.

Comparative study of Lepidium sativum orally administered seeds, hydrogel and atorvastatin on obesity of rats fed on a high fat diet.

BACKGROUND: Obesity has become a prevalent issue worldwide, leading to various complications such as hyperlipidemia, diabetes, and cardiovascular problems. Statins, as FDA approved anti-hyperlipidemic drugs, still pose some concerns upon their administration. Recently, researchers have looked for natural products as an alternative to manage hyperlipidemia and obesity. AIM: This work aimed to study the hypolipidemic effect of Lepidium sativum garden cress (GC) from different preparations; orally administered seeds, and hydrogel, in comparison to atorvastatin. METHODS: GC hydrogel was prepared from the GC aqueous extract and pharmaceutically evaluated for its pH, spreadability, seeds content, homogeneity, rheology, and in vitro release. The rat's body weight, blood glucose levels, total lipid profile, and liver biomarkers were evaluated on obese rats for one month. In addition, the histopathology study was also performed. RESULTS: GC hydrogel had acceptable pharmaceutical properties and showed a sustained release performance over 24 h. Oral and topical GC significantly reduced the lipid profiles, blood sugar and ALT, AST levels more than the negative control group and comparable to atorvastatin. It was found that oral GC showed a significant effect on the percentage decrease in the rat's body weight than the applied hydrogel. Histopathology study revealed a better outcome in the histological structure of pancreas and liver compared with rats feed on high fat diet post-treatment for one month. CONCLUSION: GC orally administered, or topically applied hydrogel could be a promising, safe alternative formulation to atorvastatin in managing hyperlipidemia and normalizing body weight of obese rats.

Nuclear power plant biological complications on marine biota from a probabilistic accident - A case study.

An accident at the Barakah Nuclear Power Plant (BNPP) would result in a significant radionuclide release into the semi-closed marine environment. In this research, the released radionuclide distribution pattern and dose rate in the Persian/Arabian (Gulf) were calculated using a combined hydrodynamic/radiobiological model. Simulations of the dispersion of artificial radionuclide concentrations were conducted using a HYSPLIT model. To assess prospective hazards in case of an incident, environmental risk from ionizing contaminants: assessment and management (ERICA) tools were used. Using the Fukushima nuclear power accident as a model, the scenario source term profile was developed. The volumetric concentrations levels of pollutants ranged between 1 × 104 mBq m-3 to 1 × 1010 mBq m-3 in the radius of 200 km after 48 h. Based on the dose rates of the various marine biotas, Polychaete worms, and Pelagic fish, they had the highest and lowest dose contribution.

Can silver nanoparticles stabilized by Fenugreek (Trigonella foenm -graecum) improve tibial bone defects repair in rabbits? A preliminary study.

Background: A fracture is considered a medical emergency leading to considerable complications. Aim: This study aimed to describe the accelerating action of Ag-NPs-FG on fracture healing in rabbits. Methods: Silver NPs (AgNPs) were reduced with fenugreek (FG), loaded into a starch gel base, and investigated for their morphology, size, and charge. Four equal groups were randomly formed of 40 adult male rabbits. A 3.5 mm diameter bone defect was created at the proximal metaphysis of the right tibia in each rabbit. Groups 1-4 were injected with placebo saline, AgNPs-FG, plain gel, and FG-gel at the bone defect zone, respectively. The healing was assessed for 8 weeks postoperatively based on the radiographic, bone turnover markers, and histopathological examinations. Results: The AgNPs-FG was obtained as a faint reddish color, spherical in shape, with an absorbance of 423 nm, a size of 118.0 ± 1.7 nm, and a surface charge of -7.8 ± 0.518 mV. The prepared AgNPs-FG hydrogel was clear, translucent, and homogenous. The pH values were 6.55-6.5 ± 0.2, the viscosity of 4,000 and 1,875 cPs, and spreadability of 1.6 ± 0.14 and 2.0 ± 0.15 for both FG and AgNPs-FG hydrogel, respectively. The radiographic union scale was significantly (p < 0.05) improved in group 2 with a significant (p < 0.05) increase in bone turnover markers was found in comparison to other treated groups. Histopathological examination revealed the formation of mature bone on the 28th postoperative day in groups 2 and 4. Conclusion: Colloidal nano-formulation of AgNPs-FG loaded hydrogel could be a promising formulation to accelerate rabbits' tibial bone healing process.

Diapocynin treatment induces functional and structural improvements in an advanced disease state in the mdx5Cv mice.

Duchenne muscular dystrophy (DMD) is the most common muscular disorder affecting children. It affects nearly 1 male birth over 5000. Oxidative stress is a pervasive feature in the pathogenesis of DMD. Recent work shows that the main generators of ROS are NADPH oxidases (NOX), suggesting that they are an early and promising target in DMD. In addition, skeletal muscles of mdx mice, a murine model of DMD, overexpress NOXes. We investigated the impact of diapocynin, a dimer of the NOX inhibitor apocynin, on the chronic disease phase of mdx5Cv mice. Treatment of these mice with diapocynin from 7 to 10 months of age resulted in decreased hypertrophy of several muscles, prevented force loss induced by tetanic and eccentric contractions, improved muscle and respiratory functions, decreased fibrosis of the diaphragm and positively regulated the expression of disease modifiers. These encouraging results ensure the potential role of diapocynin in future treatment strategies.

Radioactivity concentration levels and potential radiotoxicity risk assessment of aquatic superfoods case study of algae supplements.

It has been found that algae have a variety of health benefits, although investigations showed that they contain radiotoxic elements, including 226Ra, 232Th, 40K, and 137Cs, which may affect human health. This study is connected to activity concentration measurements of the above radionuclides in the algae supplements available in the Middle East markets. The annual effective radiation doses of measured radionuclides in analyzed algal supplements have been calculated. The highest values of annual effective doses have been estimated for 226Ra in Ecklonia (13.39 µSv/y) and for 232Th in Red Marine Algae (11.80 µSv/y), both from South Korea. In algal "superfoods", the effective dose of 137Cs is not significantly affected by the Fukushima Nuclear Power Plant. Based on these results, it can be concluded that the activity levels of radionuclides are low, the naturally occurring radionuclides provide the most effective doses, and algae supplements can be considered safe.

Synergistic effects of quercetin-loaded CoFe2O4@Liposomes regulate DNA damage and apoptosis in MCF-7 cancer cells: based on biophysical magnetic hyperthermia.

INTRODUCTION: Breast cancer (BC) is the most common malignancy in women globally. Significant progress has been made in developing structural nanoparticles (NPs) and formulations for targeted smart drug delivery (SDD) of pharmaceuticals, improving the precision of tumor cell targeting in therapy. SIGNIFICANCE: Magnetic hyperthermia (MHT) treatment using magneto-liposomes (MLs) has emerged as a promising adjuvant cancer therapy. METHODS: CoFe2O4 magnetic NPs (MNPs) were conjugated with nanoliposomes to form MLs, and the anticancer drug quercetin (Que) was loaded into MLs, forming Que-MLs composites for antitumor approach. The aim was to prepare Que-MLs for DD systems (DDS) under an alternating magnetic field (AMF), termed chemotherapy/hyperthermia (chemo-HT) techniques. The encapsulation efficiency (EE), drug loading capacity (DL), and drug release (DR) of Que and Que-MLs were evaluated. RESULTS: The results confirmed successful Que-loading on the surface of MLs, with an average diameter of 38 nm and efficient encapsulation into MLs (69%). In vitro, experimental results on MCF-7 breast cells using MHT showed high cytotoxic effects of novel Que-MLs on MCF-7 cells. Various analyses, including cytotoxicity, apoptosis, cell migration, western blotting, fluorescence imaging, and cell membrane internalization, were conducted. The Acridine Orange-ethidium bromide double fluorescence test identified 35% early and 55% late apoptosis resulting from Que-MLs under the chemo-HT group. TEM results indicated MCF-7 cell membrane internalization and digestion of Que-MLs, suggesting the presence of early endosome-like vesicles on the cytoplasmic periphery. CONCLUSIONS: Que-MLs exhibited multi-modal chemo-HT effects, displaying high toxicity against MCF-7 BC cells and showing promise as a potent cytotoxic agent for BC chemotherapy.

First report of Leishmania tropica in domestic and wild animal hosts in hyperendemic areas of human cutaneous leishmaniasis in western Yemen: a neglected tropical disease needing One Health approach.

Cutaneous leishmaniasis (CL), a neglected tropical disease, is a major public health concern in Yemen, with Leishmania tropica identified as the main causative agent. This study aims to investigate the occurrence and distribution of Leishmania parasites in domestic and wild animals in CL endemic areas in the western highlands of Yemen. A cross-sectional study was conducted in the Utmah District of western Yemen. Blood and skin scraping specimens were collected from 122 domestic and wild animals and tested for the Leishmania DNA using internal transcribed spacer 1 (ITS1) nested polymerase chain reaction. Phylogenetic analyses were performed on 20 L. tropica sequences obtained from animals in this study and 34 sequences from human isolates (collected concurrently from the same study area) retrieved from the GenBank. Overall, L. tropica was detected in 16.4% (20/122) of the examined animals, including 11 goats, two dogs, two bulls, one cow, one donkey, one rabbit, one rat and one bat. None of the examined cats and sheep was positive. The animal sequences were segregated into four different L. tropica haplotypes, with the majority of the animal (15/20) and human (32/34) sequences composed of one dominant haplotype/genotype. These findings represent the first confirmed evidence of natural L. tropica infections in different kinds of domestic and wild animals in western Yemen, suggesting these animals potentially have a role in the transmission of CL in Yemen. Therefore, a One Health approach is required for the effective prevention and control of this devastating disease among endemic populations.

Knowledge, attitude, practices and treatment-seeking behaviour concerning cutaneous leishmaniasis among rural hyperendemic communities in western Yemen.

Cutaneous leishmaniasis (CL), a neglected tropical disease (NTD), is a major public health problem in Yemen with widespread distribution in rural areas. Evaluating the knowledge and understanding of people's beliefs towards the disease is essential to the implementation of effective control measures. This study aims to assess the knowledge, attitudes, practices (KAP) and treatment-seeking behaviour concerning CL among rural populations in the western highlands of Yemen. A community-based cross-sectional study was conducted among 289 household heads in four rural areas of the Utmah District. Data were collected using a pre-tested questionnaire. All the participants had heard about the disease; however, only 9.3% attributed it to sandflies. Nearly half (48.1%) of the participants could not mention any preventive measures for CL, and nearly two-thirds (65.4%) could not do so for sandflies. The overall 'good' knowledge about CL was found to be 51.2%, and it was 33.9% for sandflies. The participants' attitude and prevention practices towards CL were not satisfactory, as only 38.1% and 16.3% had a positive attitude and good CL-related prevention practices, respectively. Moreover, 45.7% believed CL to be a stigmatising disease, and 50% had used traditional remedies to treat suspected CL lesions. Multivariate analyses showed that age, sex, presence of CL-confirmed cases in the same household, residency, occupation and monthly household income were the significant predictors associated with KAP concerning CL among the participants. The findings support an urgent need for integrated health education and community mobilisation interventions to improve awareness of these vulnerable populations about this devastating disease.

Prevalence of Diabetes, Ketosis, and Ketoacidosis and Their Correlation With Mortality in Critical COVID-19 Patients: A Single-Center Retrospective Study.

Aim We aimed to find out the prevalence of diabetes, ketosis, and ketoacidosis in coronavirus disease 2019 (COVID-19) critically ill patients and to explore the clinical impact of the development of ketosis and ketoacidosis on the outcome of COVID-19 critically ill patients and identify them as potential risk factors for these patients. Methods We collected data on COVID-19 patients admitted to the intensive care unit (ICU) retrospectively. The study population will be classified into two groups based on the presence of diabetes or ketosis. Results The study comprises data on 253 ICU patients admitted with COVID-19 pneumonia. Two hundred patients (79.05%) had diabetes or prediabetes on admission. Seventy-six patients (30%) presented with ketosis. Nine patients had progressed to diabetic ketoacidosis during their ICU stay. Concerning the outcome, among 150 patients who died (59.3%), there was significantly higher mortality among the ketotic patients (69.7%) compared to nonketotic patients (54.8%) with a P-value < 0.027. We noted that the peak blood glucose level during ICU stay was statistically significantly higher in nonsurvivors (mean 345 mg/dl) compared to survivors (mean 298 mg/dl) with a P-value of 0.006. Our data showed that peak serum levels of lactate, procalcitonin (PCT), C-reactive protein, white blood cells (WBC), D dimer, and lactate dehydrogenase strongly positively correlated to the length of ICU stay. We used the ROC curve (receiver operating characteristic curve) to assess the relation between many laboratories and mortality. We noted that uncontrolled hyperglycemia and other laboratory variables are significant predictors of mortality of COVID-19 patients (e.g., peak blood glucose (P = 0.004), PCT (P = 0.047), and P < 0.001 of other laboratories (e.g. lactate, PH, WBC, D dimer, ferritin). Conclusion We reported a high prevalence of diabetes and ketosis among COVID-19 patients admitted to the ICU. Ketosis is associated with an increased mortality risk. Uncontrolled hyperglycemia is a significant predictor of mortality in critically ill COVID-19 patients.

Effect of Stabilized nZVI Nanoparticles on the Reduction and Immobilization of Cr in Contaminated Soil: Column Experiment and Transport Modeling.

Batch and transport experiments were used to investigate the remediation of loamy sand soil contaminated with Cr(VI) using zero-valent iron nanoparticles (nZVI) stabilized by carboxymethylcellulose (CMC-nZVI). The effect of pH, ionic strength (IS), and flow rate on the removal efficiency of Cr(VI) were investigated under equilibrium (uniform transport) and non-equilibrium (two-site sorption) transport using the Hydrus-1D model. The overall removal efficiency ranged from 70 to over 90% based on the chemical characteristics of the CMC-nZVI suspension and the transport conditions. The concentration and pH of the CMC-nZVI suspension had the most significant effect on the removal efficiency and transport of Cr(VI) in the soil. The average removal efficiency of Cr(VI) was increased from 24.1 to 75.5% when the concentration of CMC-nZVI nanoparticles was increased from 10 to 250 mg L-1, mainly because of the increased total surface area at a larger particle concentration. Batch experiments showed that the removal efficiency of Cr(VI) was much larger under acidic conditions. The average removal efficiency of Cr(VI) reached 90.1 and 60.5% at pH 5 and 7, respectively. The two-site sorption model described (r2 = 0.96-0.98) the transport of Cr(VI) in soil quite well as compared to the uniform transport model (r2 = 0.81-0.98). The average retardation of Cr(VI) was 3.51 and 1.61 at pH 5 and 7, respectively, indicating earlier arrival for the breakthrough curves and a shorter time to reach maximum relative concentration at lower pH. The methodology presented in this study, combining column experiment and modeling transport using the Hydrus-1D model, successfully assessed the removal of Cr(VI) from polluted soils, offering innovative, cost-effective, and environmentally friendly remediation methodologies.

MCT4 knockdown by tumor microenvironment-responsive nanoparticles remodels the cytokine profile and eradicates aggressive breast cancer cells.

Breast cancer is a wide-spread threat to the women's health. The drawbacks of conventional treatments necessitate the development of alternative strategies, where gene therapy has regained hope in achieving an efficient eradication of aggressive tumors. Monocarboxylate transporter 4 (MCT4) plays pivotal roles in the growth and survival of various tumors, which offers a promising target for treatment. In the present study, pH-responsive lipid nanoparticles (LNPs) based on the ionizable lipid,1,2-dioleoyl-3-dimethylammonium propane (DODAP), were designed for the delivery of siRNA targeting MCT4 gene to the breast cancer cells. Following multiple steps of characterization and optimization, the anticancer activities of the LNPs were assessed against an aggressive breast cancer cell line, 4T1, in comparison with a normal cell line, LX-2. The selection of the helper phospholipid to be incorporated into the LNPs had a dramatic impact on their gene delivery performance. The optimized LNPs enabled a powerful MCT4 silencing by ∼90 % at low siRNA concentrations, with a subsequent ∼80 % cytotoxicity to 4T1 cells. Meanwhile, the LNPs demonstrated a 5-fold higher affinity to the breast cancer cells versus the normal cells, in which they had a minimum effect. Moreover, the MCT4 knockdown by the treatment remodeled the cytokine profile in 4T1 cells, as evidenced by 90 % and ∼64 % reduction in the levels of TNF-α and IL-6; respectively. The findings of this study are promising for potential clinical applications. Furthermore, the simple and scalable delivery vector developed herein can serve as a breast cancer-targeting platform for the delivery of other RNA therapeutics.

Regiodivergent biosynthesis of bridged bicyclononanes.

Medicinal compounds from plants include bicyclo[3.3.1]nonane derivatives, the majority of which are polycyclic polyprenylated acylphloroglucinols (PPAPs). Prototype molecules are hyperforin, the antidepressant constituent of St. John's wort, and garcinol, a potential anticancer compound. Their complex structures have inspired innovative chemical syntheses, however, their biosynthesis in plants is still enigmatic. PPAPs are divided into two subclasses, named type A and B. Here we identify both types in Hypericum sampsonii plants and isolate two enzymes that regiodivergently convert a common precursor to pivotal type A and B products. Molecular modelling and substrate docking studies reveal inverted substrate binding modes in the two active site cavities. We identify amino acids that stabilize these alternative binding scenarios and use reciprocal mutagenesis to interconvert the enzymatic activities. Our studies elucidate the unique biochemistry that yields type A and B bicyclo[3.3.1]nonane cores in plants, thereby providing key building blocks for biotechnological efforts to sustainably produce these complex compounds for preclinical development.

Unlocking the secrets: exploring the influence of the aryl hydrocarbon receptor and microbiome on cancer development.

Gut microbiota regulates various aspects of human physiology by producing metabolites, metabolizing enzymes, and toxins. Many studies have linked microbiota with human health and altered microbiome configurations with the occurrence of several diseases, including cancer. Accumulating evidence suggests that the microbiome can influence the initiation and progression of several cancers. Moreover, some microbiotas of the gut and oral cavity have been reported to infect tumors, initiate metastasis, and promote the spread of cancer to distant organs, thereby influencing the clinical outcome of cancer patients. The gut microbiome has recently been reported to interact with environmental factors such as diet and exposure to environmental toxicants. Exposure to environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) induces a shift in the gut microbiome metabolic pathways, favoring a proinflammatory microenvironment. In addition, other studies have also correlated cancer incidence with exposure to PAHs. PAHs are known to induce organ carcinogenesis through activating a ligand-activated transcriptional factor termed the aryl hydrocarbon receptor (AhR), which metabolizes PAHs to highly reactive carcinogenic intermediates. However, the crosstalk between AhR and the microbiome in mediating carcinogenesis is poorly reviewed. This review aims to discuss the role of exposure to environmental pollutants and activation of AhR on microbiome-associated cancer progression and explore the underlying molecular mechanisms involved in cancer development.

Adhesion of Candida Albicans to digital versus conventional acrylic resins: a systematic review and meta-analysis.

BACKGROUND: The present systematic review and meta-analysis investigated the available evidence about the adherence of Candida Albicans to the digitally-fabricated acrylic resins (both milled and 3D-printed) compared to the conventional heat-polymerized acrylic resins. METHODS: This study followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA). A comprehensive search of online databases/search tools (Web of Science, Scopus, PubMed, Ovid, and Google Scholar) was conducted for all relevant studies published up until May 29, 2023. Only in-vitro studies comparing the adherence of Candida albicans to the digital and conventional acrylic resins were included. The quantitative analyses were performed using RevMan v5.3 software. RESULTS: Fourteen studies were included, 11 of which were meta-analyzed based on Colony Forming Unit (CFU) and Optical Density (OD) outcome measures. The pooled data revealed significantly lower candida colonization on the milled digitally-fabricated compared to the heat-polymerized conventionally-fabricated acrylic resin materials (MD = - 0.36; 95%CI = - 0.69, - 0.03; P = 0.03 and MD = - 0.04; 95%CI = - 0.06, - 0.01; P = 0.0008; as measured by CFU and OD respectively). However, no differences were found in the adhesion of Candida albicans between the 3D-printed digitally-fabricated compared to the heat-polymerized conventionally-fabricated acrylic resin materials (CFU: P = 0.11, and OD: P = 0.20). CONCLUSION: The available evidence suggests that candida is less likely to adhere to the milled digitally-fabricated acrylic resins compared to the conventional ones.

Plasma Growth Hormone as a Prognostic Biomarker to Durvalumab and Tremelimumab in Patients with Advanced Hepatocellular Carcinoma.

Introduction: In this study, we explored the potential of plasma growth hormone (GH) as a prognostic biomarker in patients with advanced HCC treated with durvalumab plus tremelimumab (D+T). Methods: In this study, we included 16 patients with advanced HCC who received D+T at MD Anderson Cancer Center between 2022 and 2023 and had plasma GH measurements recorded before treatment. Plasma GH levels were measured from prospectively collected blood samples and were correlated with progression-free survival (PFS) and overall survival (OS). The cutoff for normal GH levels in women and men was defined as ≤3.7 µg/L and ≤0.9 µg/L, respectively. The Kaplan-Meier method was employed to compute the median OS and PFS, while the Log rank test was applied to compare the survival outcomes between the GH-high and GH-low groups. Results: Sixteen patients were included in this analysis, two female and fourteen male, with a median age of 65.5 years. At the time of the analysis, the 6-month OS rate was 100% among GH-low patients (6 patients) and 30% among GH-high patients (10 patients). OS was significantly longer in GH-low patients (not evaluable) compared to GH-high patients (3.94 months) (p = 0.030). PFS was also significantly longer in GH-low patients (not evaluable) compared to the GH-high patients (1.87 months) (p = 0.036). Conclusion: Plasma GH is a prognostic biomarker in patients with advanced HCC treated with D+T. Given the relatively small patient cohort size, this finding should be further validated in larger randomized clinical trials in advanced HCC patients.

Apabetalone (RVX-208): A Potential Epigenetic Therapy for the Treatment of Cardiovascular, Renal, Neurological, Viral, and Cancer Disorders.

Bromodomain and extra-terminal domain proteins (BET proteins) are epigenetic reader proteins that have been implicated in regulating gene expression through binding to chromatin and interaction with transcription factors. These proteins are located in the nucleus and are responsible for recognizing acetylated lysine residues on histones, reading epigenetic messages, recruiting key transcription factors, and thereby regulating gene expression. BET proteins control the transcription of genes responsible for maladaptive effects in inflammation, cancer, and renal and cardiovascular diseases. Given the multifaceted role of BET proteins in the pathogenesis of various diseases, several small molecule inhibitors of BET proteins have been developed as potential therapeutic targets for treating different diseases in recent years. However, while many nonselective BET inhibitors are indicated for the treatment of cancer, a selective BET inhibitor, apabetalone, is the only oral BET inhibitor in phase III clinical trials for the treatment of cardiovascular diseases and others. Thus, this review aims to present and discuss the preclinical and clinical evidence for the beneficial effects and mechanism of action of apabetalone for treating various diseases.

Efbalropendekin Alfa enhances human natural killer cell cytotoxicity against tumor cell lines in vitro.

IL-15 has shown preclinical activity by enhancing the functional maturation of natural killer (NK) cells. Clinical evaluation of the potential anticancer activity of most cytokines, including IL-15, has been limited by low tolerability and rapid in vivo clearance. Efbalropendekin Alfa (XmAb24306) is a soluble IL15/IL15-receptor alpha heterodimer complex fused to a half-life extended Fc domain (IL15/IL15Rα-Fc), engineered with mutations to reduce IL-15 affinity for CD122. Reduced affinity drives lower potency, leading to prolonged pharmacodynamic response in cynomolgus monkeys. We show that in vitro, human NK cells treated with XmAb24306 demonstrate enhanced cytotoxicity against various tumor cell lines. XmAb24306-treated NK cells also exhibit enhanced killing of 3D colorectal cancer spheroids. Daratumumab (dara), a monoclonal antibody (mAb) that targets CD38 results in antibody-dependent cellular cytotoxicity (ADCC) of both multiple myeloma (MM) cells and NK cells. Addition of XmAb24306 increases dara-mediated NK cell ADCC against various MM cell lines in vitro. Because NK cells express CD38, XmAb24306 increases dara-mediated NK cell fratricide, but overall does not negatively impact the ADCC activity against a MM cell line likely due to increased NK cell activity of the surviving cells. These data show that XmAb24306 increases direct and ADCC-mediated human NK cell cytotoxicity in vitro.

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Microsatellite-based analysis reveals Aedes aegypti populations in the Kingdom of Saudi Arabia result from colonization by both the ancestral African and the global domestic forms.

The Aedes aegypti (Linnaeus, 1762) mosquito is the main vector of dengue, chikungunya and Zika and is well established today all over the world. The species comprises two forms: the ancestral form found throughout Africa and a global domestic form that spread to the rest of the tropics and subtropics. In Saudi Arabia, A. aegypti has been known in the southwest since 1956, and previous genetic studies clustered A. aegypti from Saudi Arabia with the global domestic form. The purpose of this study was to assess the genetic structure of A. aegypti in Saudi Arabia and determine their geographic origin. Genetic data for 17 microsatellites were collected for A. aegypti ranging from the southwestern highlands of Saudi Arabia on the border of Yemen to the north-west in Madinah region as well as from Thailand and Uganda populations (as representatives of the ancestral African and global domestic forms, respectively). The low but significant level of genetic structuring in Saudi Arabia was consistent with long-distance dispersal capability possibly through road connectivity and human activities, that is, passive dispersal. There are two main genetic groupings in Saudi Arabia, one of which clusters with the Ugandan population and the other with the Thailand population with many Saudi Arabian individuals having mixed ancestry. The hypothesis of genetic admixture of the ancestral African and global domestic forms in Saudi Arabia was supported by approximate Bayesian computational analyses. The extent of admixture varied across Saudi Arabia. African ancestry was highest in the highland area of the Jazan region followed by the lowland Jazan and Sahil regions. Conversely, the western (Makkah, Jeddah and Madinah) and Najran populations corresponded to the global domesticated form. Given potential differences between the forms in transmission capability, ecology and behaviour, the findings here should be taken into account in vector control efforts in Saudi Arabia.