Environmental and human health risk of potentially toxic metals in freshwater and brackish water Nile tilapia (Oreochromis niloticus) aquaculture.

Tilapia aquaculture is rapidly expanding worldwide, particularly in Bangladesh. However, metal pollution in aquaculture presents significant environmental and human health risks. This study aimed to evaluate the concentrations of 13 potentially toxic metals (As, Be, Cd, Co, Cr, Cu, Hg, Ni, Pb, V, Mn, Se, and Zn) in Nile tilapia (Oreochromis niloticus), surface water, and sediment from freshwater and brackish water aquaculture ponds. The study also assessed the associated environmental and human health risks. Samples of tilapia, water, and sediment were collected between October and November 2021 and analyzed using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The estimated daily intake (EDI) of As, Cr, Pb, Se, and Zn in tilapia muscle of both freshwater and brackish water, as well as Cd and Ni in brackish water, exceeded recommended EDI values. The Target Hazard Quotient (THQ) was less than 1 for most metals, except for As in brackish water tilapia and Cr in both freshwater and brackish water tilapia, indicating potential health risks. The Target Cancer Risk (TR) values for As in both freshwater and brackish water tilapia, and for Cr and Ni in freshwater tilapia, exceeded acceptable ranges. While the concentrations of metals in surface water of both freshwater and brackish water tilapia farms varied, all mean concentrations were below WHO recommended limits. The contamination factor (Cf) values were less than 1 for all metals in both types of aquaculture ponds, except for Zn in freshwater sediment and Se in brackish water sediment. Additionally, the calculated risk indices including the Pollution Load Index (PLI), Geoaccumulation Index (Igeo), Ecological Risk Factor (Er), and Potential Ecological Risk Factor (PER) for sediment were below the risk thresholds values (PLI < 1, Igeo < 0, Er < 40, and PER < 150). The significant positive correlations were found between tilapia muscle and the sediment of the respective ponds for arsenic (As) (ρ= 0.8, p<0.002) and Cr (ρ= 0.7, p<0.02). Although the levels of studied metals in water and sediment from freshwater and brackish water aquaculture ponds were generally within recommended guidelines, this study underscores the need for continuous monitoring and preventative measures, particularly to address elevated levels of As and Cr in tilapia muscle, which may pose potential risks to human health.

Microbiome analysis revealing microbial interactions and secondary bacterial infections in COVID-19 patients comorbidly affected by Type 2 diabetes.

The mortality of coronavirus disease 2019 (COVID-19) disease is very high among the elderly or individuals having comorbidities such as obesity, cardiovascular diseases, lung infections, hypertension, and/or diabetes. Our study characterizes the metagenomic features in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients with or without type 2 diabetes, to identify the microbial interactions associated with its fatal consequences.This study compared the baseline nasopharyngeal microbiome of SARS-CoV-2-infected diabetic and nondiabetic patients with controls adjusted for age and gender. The metagenomics based on next-generation sequencing was performed using Ion GeneStudio S5 Series and the data were analyzed by the Vegan-package in R. All three groups possessed significant bacterial diversity and dissimilarity indexes (p < 0.05). Spearman's correlation coefficient network analysis illustrated 183 significant positive correlations and 13 negative correlations of pathogenic bacteria (r = 0.6-1.0, p < 0.05), and 109 positive correlations between normal flora and probiotic bacteria (r > 0.6, p < 0.05). The SARS-CoV-2 diabetic group exhibited a significant increase in pathogens and secondary infection-causing bacteria (p < 0.05) with a simultaneous decrease of normal flora (p < 0.05). The dysbiosis of the bacterial community might be linked with severe consequences of COVID-19-infected diabetic patients, although a few probiotic strains inhibited numerous pathogens in the same pathological niches. This study suggested that the promotion of normal flora and probiotics through dietary supplementation and excessive inflammation reduction by preventing secondary infections might lead to a better outcome for those comorbid patients.

Spatiotemporal distribution and pollution assessment of trace metals in the Buriganga River, Bangladesh.

The Buriganga River plays a key role in the socioeconomic structure of Dhaka, the capital of Bangladesh. However, this river is severely polluted and is considered one of the most polluted in the world. Therefore, this study aimed to assess the concentrations of various metals in the Buriganga River. A study was conducted from August 2019 to February 2020 to determine the concentrations of 16 metals in water samples (n = 210) collected from 10 distinct sites in the Buriganga River. The mean values for the concentrations of Cr, Mn, Ni, Zn, As, Se, Cd, Sb, and Pb in river water were above the guideline values prescribed by the WHO, Japan, and Bangladesh. Moreover, the fraction ratios of Be, Cr, Co, Ni, Cu, Zn, Se, Mo, Ag, Cd, Sb, and Pb were high (>0.85); consequently, these metals could accumulate at high concentrations in river sediments. Assessment using the single-factor pollution index allowed the classification of the pollution level as 'serious pollution' for Sb and 'heavy pollution' for Cd, Ni, and Pb. The trace metal concentrations in this river imply that crops cultivated along the river using river water may also be contaminated with trace metals.

An open label, randomized phase 2 trial assessing the impact of food on the tolerability of abemaciclib in patients with advanced breast cancer.

PURPOSE: Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity. METHODS: This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200 mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥ Grade 3), prolonged (> 7 days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported. RESULTS: Incidence of investigator assessed severe diarrhea (Grade ≥ 3) was 1.4% (1 patient in Arm 1). Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. No patient discontinued treatment due to diarrhea. Nine patients (12.7%) had a dose reduction, and 7 patients (9.9%) had a dose omission due to diarrhea. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms. CONCLUSION: The results suggest that diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications.

Occurrence, potential source, and cancer risk of PM2.5-bound polycyclic aromatic hydrocarbons and their halogenated derivatives in Shizuoka, Japan, and Dhaka, Bangladesh.

Because of their unintentional formation and low vapor pressure, polycyclic aromatic hydrocarbons (PAHs) and their halogenated derivatives (XPAHs) in the atmosphere are distributed primarily to aerosolized particles with an aerodynamic diameter less than 2.5 µm (PM2.5). However, no information is available regarding the occurrence of PM2.5-bound PAHs and XPAHs in Bangladesh, one of the most highly PM2.5-polluted regions worldwide. In this study, we investigated the occurrence of PM2.5-bound PAHs and XPAHs in the atmospheres of Dhaka in Bangladesh and Shizuoka in Japan (as a reference) and estimated their incremental lifetime cancer risks (ILCRs). In addition, we statistically estimated the potential sources of PM2.5-bound PAHs and XPAHs by using principal component analysis and positive matrix factorization. The median concentration of total PM2.5-bound PAHs and XPAHs in Bangladesh was 24.2 times that in Japan. The estimated potential sources of PAHs clearly differed between Japan and Bangladesh, whereas those of XPAHs were largely (>80%) unknown in both countries. The median ILCR in Bangladesh was 2.81 × 10-3, which greatly exceeded the upper limit of acceptable risk (10-4). These results indicate that comprehensive monitoring and control of atmospheric PM2.5-bound PAHs and XPAHs are needed urgently, especially in highly polluted countries.

Distribution, Source Apportionment, and Risk Assessment of Polycyclic Aromatic Hydrocarbons (PAHs) in the Surficial Sediments from the Coastal Areas of Bangladesh.

The surficial sediments were collected in winter and summer (2015) from the coastal areas of Bangladesh and analyzed for 16 USEPA priority polycyclic aromatic hydrocarbons (PAHs). The total concentration of PAHs (∑PAHs) were 349.8-11,058.8 and 199.9-17,089.1 ng/g dry weight (dw) in winter and summer, respectively. Sediements from the areas with recent urbanization and industrialization (Chittagong, Cox's Bazar, and Sundarbans) were more contaminated with PAHs than the unindustrialized area (Meghna Estuary). The concentrations of ∑PAHs were slightly higher in summer than those in winter, but the seasonal variations were not statistically significant (p > 0.05). Molecular ratios suggested mixed sources of PAHs in the Bangladeshi coastal areas with a slight imposition of pyrolytic inputs closely related to shipping and fishing activities as well as industrial and municipal sewage discharge. According to ecological risk assessment, the measured levels of sedimentary PAHs exceeded some of the existing national and international environmental quality guidelines/standards, and thus might cause acute biological damage in the studied areas of the Bay of Bengal coast of Bangladesh.

Occurrence and ecological risk of pharmaceuticals in river surface water of Bangladesh.

Pharmaceutical contamination in the aquatic environment is a global issue that affects aquatic animals, micro-organisms and human health. The occurrence and preliminary ecological risk of 12 (11 antibiotics and 1 antiepileptic drug) pharmaceuticals were investigated for the first time in the surface water of the old Brahmaputra River, where open-water-fed aquaculture activities are being practiced in Bangladesh. The pharmaceuticals were quantified by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS), operated with positive electrospray ionization (ESI+) and a multiple reaction monitoring (MRM) mode. Nine pharmaceuticals were detected in the river surface water, whereas three were below the limit of detection (LOD). Metronidazole was detected in all the samples with concentrations ranging from 0.05 to 13.51 ng L-1. Trimethoprim had the second highest frequency of detection (95%) with the highest concentration (17.20 ng L-1). The ranges of concentration and detection frequency of sulfonamides and macrolides were

The Physiological and Ergogenic Effects of Khat (Catha edulis Forsk) Extract.

BACKGROUND: Khat (Catha edulis Forsk) is a natural psychoactive substance which contains two main addictive substances; Cathine and Cathinone. Khat is widely used in east Africa and southern Arabian Peninsula. Khat chewers believe that it improves work capacity and increases energy level and alertness. That is why we aimed in this study to investigate the physiological and ergogenic effects of khat extract. METHODS: This study is an experimental study conducted at the Substance Abuse Research Centre in Jazan University, Saudi Arabia. Thirty healthy young volunteers were randomly assigned into two experimental groups. The first group ingested 45 g of grounded khat leaves extract mixed with juice in the first session then placebo (juice only) in the second session. While the second group ingested the placebo in the first session and the grounded khat leaves with juice in the second session. Experiments were done between December 2012 and March 2013. We recorded the blood pressure, heart rate, grip strength, and reaction time every 15 min for 75 min after each ingestion. The study proposal was reviewed and approved by Research Ethics Committee (REC) of the Medical Research Centre in Jazan University. RESULTS: The results showed the consumption of 45 g of grounded khat leaves contributed to the increase in blood pressure (SBP & DBP) and reaction time (p < 0.05); but had no significant effect on heart rate and grip strength (p > 0.05). CONCLUSIONS: The findings of this study showed that Khat has an acute effect on some physiological parameters. These findings support the prohibition of cathinone and cathine by the World Anti-Doping Agency (WADA, 2016).

Mesenchymal Stem Cells Isolated From Human Gliomas Increase Proliferation and Maintain Stemness of Glioma Stem Cells Through the IL-6/gp130/STAT3 Pathway.

Although mesenchymal stem cells (MSCs) have been implicated as stromal components of several cancers, their ultimate contribution to tumorigenesis and their potential to drive cancer stem cells, particularly in the unique microenvironment of human brain tumors, remain largely undefined. Consequently, using established criteria, we isolated glioma-associated-human MSCs (GA-hMSCs) from fresh human glioma surgical specimens for the first time. We show that these GA-hMSCs are nontumorigenic stromal cells that are phenotypically similar to prototypical bone marrow-MSCs. Low-passage genomic sequencing analyses comparing GA-hMSCs with matched tumor-initiating glioma stem cells (GSCs) suggest that most GA-hMSCs (60%) are normal cells recruited to the tumor (group 1 GA-hMSCs), although, rarely (10%), GA-hMSCs may differentiate directly from GSCs (group 2 GA-hMSCs) or display genetic patterns intermediate between these groups (group 3 GA-hMSCs). Importantly, GA-hMSCs increase proliferation and self-renewal of GSCs in vitro and enhance GSC tumorigenicity and mesenchymal features in vivo, confirming their functional significance within the GSC niche. These effects are mediated by GA-hMSC-secreted interleukin-6, which activates STAT3 in GSCs. Our results establish GA-hMSCs as a potentially new stromal component of gliomas that drives the aggressiveness of GSCs, and point to GA-hMSCs as a novel therapeutic target within gliomas.

Advancing breast ultrasound diagnostics through hybrid deep learning models.

Today, doctors rely heavily on medical imaging to identify abnormalities. Proper classification of these abnormalities enables them to take informed actions, leading to early diagnosis and treatment. This paper introduces the "EfficientKNN" model, a novel hybrid deep learning approach that combines the advanced feature extraction capabilities of EfficientNetB3 with the simplicity and effectiveness of the k-Nearest Neighbors (k-NN) algorithm. Initially, EfficientNetB3, pre-trained on ImageNet, is repurposed to serve as a feature extractor. Subsequently, a GlobalAveragePooling2D layer is applied, followed by an optional Principal Component Analysis (PCA) to reduce dimensionality while preserving critical information. PCA is used selectively when deemed necessary. The extracted features are then classified using an optimized k-NN algorithm, fine-tuned through meticulous cross-validation.Our model underwent rigorous training using a curated dataset containing benign, malignant, and normal medical images. Data augmentation techniques, including rotations, shifts, flips, and zooms, were employed to help the model generalize and efficiently handle new, unseen data. To enhance the model's ability to identify the important features necessary for accurate predictions, the dataset was refined using segmentation and overlay techniques. The training utilized an ensemble of optimization algorithms-SGD, Adam, and RMSprop-with hyperparameters set at a learning rate of 0.00045, a batch size of 32, and up to 120 epochs, facilitated by early stopping to prevent overfitting.The results demonstrate that the EfficientKNN model outperforms traditional models such as VGG16, AlexNet, and VGG19 in terms of accuracy, precision, and F1-score. Additionally, the model showed better results compared to EfficientNetB3 alone. Achieving a 100 % accuracy rate on multiple tests, the EfficientKNN model has significant potential for real-world diagnostic applications. This study highlights the model's scalability, efficient use of cloud storage, and real-time prediction capabilities, all while minimizing computational demands.By integrating the strengths of EfficientNetB3's deep learning architecture with the interpretability of k-NN, EfficientKNN presents a significant advancement in medical image classification, promising improved diagnostic accuracy and clinical applicability.

Evaluation of the potentials of rice varieties and water management practices for reducing human health risks associated with polluted river water irrigated rice in Bangladesh.

The consumption of arsenic and trace-metal-contaminated rice is a human health concern worldwide, particularly in Bangladesh. In this study, the effects of rice varieties and water management practices on the concentrations of arsenic and trace metals in rice grains were investigated to reduce human health risks related to rice consumption. In addition, the performance of risk reduction using the optimum combination of rice variety and water management practices was quantitatively assessed using Monte Carlo simulation, in which non-carcinogenic and carcinogenic risk distributions under the status quo and the optimum combination were compared. The experimental results revealed that Dular and BRRI dhan45 (rice varieties) cultivated under alternate wetting and drying (AWD) and continuous flooding (CF) conditions showed the lowest hazard quotient (HQ) values for copper, cadmium, and arsenic and the lowest target cancer risk (TR) for arsenic. In Dular and BRRI dhan45 (AWD and CF) varieties, the proportion of the population for which HQs exceeded 1.0 (the reference value) tended to decrease (except for arsenic), compared with populations for which the rice varieties and water management practices were not specified. These results suggest that the use of optimum combinations of rice varieties and water management practices could reduce non-carcinogenic and carcinogenic risks associated with arsenic and trace metals uptake via rice grain consumption by the Bangladeshi people.

Tumor-specific polycistronic miRNA delivered by engineered exosomes for the treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs. METHODS: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding 3 miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/VSVg) in their structure (eExos+pPolymiR) to enhance function. RESULTS: Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all 3 miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail. CONCLUSION: eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform, represents a new and potentially powerful anti-GBM therapeutic.

Genome sequence of white spot syndrome virus (WSSV) infecting cultured black tiger shrimp (Penaeus monodon) in Bangladesh.

The white spot syndrome virus (WSSV) is a causative agent of white spot disease (WSD) in crustaceans, especially in cultivated black tiger shrimp (Penaeus monodon), leading to significant economic losses in the aquaculture sector. The present study describes four whole genome sequences of WSSV obtained from coastal regions of Bangladesh.

In silico analysis of a novel hypothetical protein (YP_498675.1) from Staphylococcus aureus unravels the protein of tryptophan synthase beta superfamily (Try-synth-beta_ II).

BACKGROUND: Staphylococcus aureus is a gram-positive spherical bacteria and the most common cause of nosocomial infections in the world. Given its clinical significance, the genome sequence of S. aureus has been elucidated to enhance our comprehension of its lifestyle and pathogenicity. The research aimed to summarize a potential hypothetical protein that may play an important role in S. aureus virulence and pathogenicity, covering its anticipated structure, probable biological functions, and importance in this context. RESULTS: A hypothetical protein, YP_498675.1 with 281 amino acid residues of S. aureus, was chosen for analysis and modeling by several bioinformatics tools and databases in this work. According to primary and secondary structure analyses, YP_498675.1 is a stable hydrophilic protein with a significant proportion of α-helices. Subcellular localization predictions by CELLO, PSORTb, and SOSUI server indicate that it is a cytoplasmic protein. NCBI-CDD, Pfam, and InterProScan functional genomics research revealed that the hypothetical protein may include the pyridoxal phosphate (PLP)-dependent 2, 3-diaminopropionate biosynthesis protein SbnA domain. In the homology modeling method, the HHpred server was employed to create its 3D structure using the template structure of a Staphyloferrin B precursor biosynthetic enzyme SbnA bound to PLP (PDB ID: 5D84_A), an X-ray diffraction model having 100% sequence identity with the hypothetical protein. After energy minimization, several quality assessments and validation factors determined that the generated protein model was reliable and of reasonable quality. CONCLUSION: The present study has characterized and functionally annotated the hypothetical protein YP_498675.1 of S. aureus. Further experimental validation would aid in determining the actual function of YP_498675.1 as well as confirm the protein's value as a therapeutic target.

Association of Antibacterial Susceptibility Profile with the Prevalence of Genes Encoding Efflux Proteins in the Bangladeshi Clinical Isolates of Staphylococcus aureus.

Expelling antibiotic molecules out of the cell wall through multiple efflux pumps is one of the potential mechanisms of developing resistance against a wide number of antibiotics in Staphylococcus aureus. The aim of this study was to investigate the association between the antibiotic susceptibility profile and the prevalence of different efflux pump genes i.e., norA, norB, norC, mepA, sepA, mdeA, qacA/B, and smr in the clinical isolates of S. aureus. Sixty clinical isolates were collected from a tertiary level hospital in Bangladesh. The disc diffusion method using ten antibiotics of different classes was used to discern the susceptibility profile. polymerase chain reaction (PCR) was employed to observe the resistance patterns and to detect the presence of plasmid and chromosomal encoded genes. Among the clinical isolates, 60% (36 out of 60) of the samples were Methicillin-resistant Staphylococcus aureus (MRSA), whereas 55% (33 out of 60) of the bacterial samples were found to be multi-drug resistant. The bacteria showed higher resistance to vancomycin (73.33%), followed by ciprofloxacin (60%), cefixime (53.33%), azithromycin (43.33%), and amoxicillin (31.67%). The prevalence of the chromosomally-encoded efflux genes norA (91.67%), norB (90%), norC (93.33%), mepA (93.33%), sepA (98.33%), and mdeA (93.33%) were extremely high with a minor portion of them carrying the plasmid-encoded genes qacA/B (20%) and smr (8.33%). Several genetic combinations of efflux pump genes were revealed, among which norA + norB + norC + mepA + sepA + mdeA was the most widely distributed combination among MRSA and MSSA bacteria that conferred resistance against ciprofloxacin and probably vancomycin. Based on the present study, it is evident that the presence of multiple efflux genes potentiated the drug extrusion activity and may play a pivotal role in the development of multidrug resistance in S. aureus.

A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer.

BACKGROUND: Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). METHODS: Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m(2) intravenously [IV], 5-fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2) IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. RESULTS: Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin-related death occurred because of arrhythmia. CONCLUSIONS: Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone.

Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum-based chemotherapy is often a first-line treatment. Pemetrexed has shown single-agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed-cisplatin for SCCHN. METHODS: In a double-blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m(2) ) plus cisplatin (75 mg/m(2) ; n = 398) or placebo plus cisplatin (75 mg/m(2) ; n = 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed-cisplatin arm and 6.3 months in the placebo-cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75-1.02; P = .082). Median progression-free survival (PFS, months) was similar in both treatment arms (pemetrexed-cisplatin, 3.6; placebo-cisplatin, 2.8; HR, 0.88; 95% CI, 0.76-1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed-cisplatin (n = 347) led to longer OS and PFS than placebo-cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed-cisplatin (n = 86) resulted in longer OS and PFS than placebo-cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed-cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed-cisplatin compared with placebo-cisplatin did not significantly improve survival for the intent-to-treat population. However, in a prespecified subgroup analysis, pemetrexed-cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers.

Antibiotics, antibiotic-resistant bacteria, and resistance genes in aquaculture: risks, current concern, and future thinking.

Aquaculture is remarkably one of the most promising industries among the food-producing industries in the world. Aquaculture production as well as fish consumption per capita have been dramatically increasing over the past two decades. Shifting of culture method from semi-intensive to intensive technique and applying of antibiotics to control the disease outbreak are the major factors for the increasing trend of aquaculture production. Antibiotics are usually present at subtherapeutic levels in the aquaculture environment, which increases the selective pressure to the resistant bacteria and stimulates resistant gene transfer in the aquatic environment. It is now widely documented that antibiotic resistance genes and resistant bacteria are transported from the aquatic environment to the terrestrial environment and may pose adverse effects on human and animal health. However, data related to antibiotic usage and bacterial resistance in aquaculture is very limited or even absent in major aquaculture-producing countries. In particular, residual levels of antibiotics in fish and shellfish are not well documented. Recently, some of the countries have already decided the maximum residue levels (MRLs) of antibiotics in fish muscle or skin; however, many antibiotics are yet not to be decided. Therefore, an urgent universal effort needs to be taken to monitor antibiotic concentration and resistant bacteria particularly multiple antibiotic-resistant bacteria and to assess the associated risks in aquaculture. Finally, we suggest to take an initiative to make a uniform antibiotic registration process, to establish the MRLs for fish/shrimp and to ensure the use of only aquaculture antibiotics in fish and shellfish farming globally.

Abemaciclib in combination with pembrolizumab for HR+, HER2- metastatic breast cancer: Phase 1b study.

This nonrandomized, open-label, multi-cohort Phase 1b study (NCT02779751) investigated the safety and efficacy of abemaciclib plus pembrolizumab with/without anastrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) without prior CDK4 and 6 inhibitor exposure. Patients were divided into two cohorts: treatment naïve (cohort 1) and pretreated (cohort 2). Patients received abemaciclib plus pembrolizumab with (cohort 1) or without (cohort 2) anastrozole over 21-day cycles. The primary objective was safety, and secondary objectives included efficacy and pharmacokinetics (PK). Cohort 1/2 enrolled 26/28 patients, respectively. Neutropenia (30.8/28.6%), AST increase (34.6/17.9%), ALT increase (42.3/10.7%), and diarrhea (3.8/10.7%) were the most frequent grade ≥3 adverse events in cohort 1/2, respectively. A total of two deaths occurred, which investigators attributed to treatment-related adverse events (AEs), both in cohort 1. Higher rates of all grade and grade ≥3 interstitial lung disease (ILD)/pneumonitis were observed compared to previously reported with abemaciclib and pembrolizumab monotherapy. The PK profiles were consistent between cohorts and with previous monotherapy studies. In cohorts 1/2, the overall response rate and disease control rate were 23.1/28.6% and 84.6/82.1%, respectively. Median progression-free survival and overall survivals were 8.9 (95% CI: 3.9-11.1) and 26.3 months (95% CI: 20.0-31.0) for cohort 2; cohort 1 data are immature. Abemaciclib plus pembrolizumab demonstrated antitumor activity, but high rates of ILD/pneumonitis and severe transaminase elevations occurred with/without anastrozole compared to the previous reporting. Benefit/risk analysis does not support further evaluation of this combination in the treatment of HR+, HER2- MBC.

Characterization of patient-derived bone marrow human mesenchymal stem cells as oncolytic virus carriers for the treatment of glioblastoma.

OBJECTIVE: Delta-24-RGD is an oncolytic adenovirus that is capable of replicating in and killing human glioma cells. Although intratumoral delivery of Delta-24-RGD can be effective, systemic delivery would improve its clinical application. Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) obtained from healthy donors have been investigated as virus carriers. However, it is unclear whether BM-hMSCs can be derived from glioma patients previously treated with marrow-toxic chemotherapy or whether such BM-hMSCs can deliver oncolytic viruses effectively. Herein, the authors undertook a prospective clinical trial to determine the feasibility of obtaining BM-hMSCs from patients with recurrent malignant glioma who were previously exposed to marrow-toxic chemotherapy. METHODS: The authors enrolled 5 consecutive patients who had been treated with radiation therapy and chemotherapy. BM aspirates were obtained from the iliac crest and were cultured to obtain BM-hMSCs. RESULTS: The patient-derived BM-hMSCs (PD-BM-hMSCs) had a morphology similar to that of healthy donor-derived BM-hMSCs (HD-BM-hMSCs). Flow cytometry revealed that all 5 cell lines expressed canonical MSC surface markers. Importantly, these cultures could be made to differentiate into osteocytes, adipocytes, and chondrocytes. In all cases, the PD-BM-hMSCs homed to intracranial glioma xenografts in mice after intracarotid delivery as effectively as HD-BM-hMSCs. The PD-BM-hMSCs loaded with Delta-24-RGD (PD-BM-MSC-D24) effectively eradicated human gliomas in vitro. In in vivo studies, intravascular administration of PD-BM-MSC-D24 increased the survival of mice harboring U87MG gliomas. CONCLUSIONS: The authors conclude that BM-hMSCs can be acquired from patients previously treated with marrow-toxic chemotherapy and that these PD-BM-hMSCs are effective carriers for oncolytic viruses.