A signature of five 7-methylguanosine-related genes is a prognostic marker for lung squamous cell carcinoma.

Background: N7-methylguanosine (m7G) is an important posttranscriptional modification affecting mRNA and tRNA functions and stability. The genes regulating the m7G process have been previously found involved in the carcinogenesis process. We aimed to analyze the role of m7G-related genes as potential prognostic markers for lung squamous cell carcinoma (LSCC). Methods: Twenty-nine m7G-related genes were selected for the analysis in the LSCC cohort of the Cancer Genome Atlas (TCGA). Univariate, multivariate, and Kaplan-Meier analyses were used to evaluate the predictive value of risk model developed with m7G signature for overall survival (OS).. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of differentially expressed genes (DEGs) were performed for high- and low-risk LSCC groups. Results: We identified 17 differentially expressed m7G methylation-related genes in LSCC versus normal tissues. The expression of five m7G-related genes (EIF3D, LSM1, NCBP2, NUDT10, and NUDT11) was identified as an independent prognostic marker for OS in LSCC patients. A risk model with these five m7G-related genes predicted 2-, and 3-year survival rates of 0.623 and 0.626, respectively. The risk score significantly correlated with OS: LSCC patients with a higher risk score had shorter OS (P<0.01) and it was associated with lower immune response (P<0.01). Conclusions: We developed a novel m7G-related gene signature that can be of great utility to predict the prognosis for patients with LSCC.

Association between hospitalizations for asthma exacerbation and weather conditions in Qingdao: an ecological study.

Background: The hospitalization for asthma exacerbation has varied with seasons, however, the underlying weather reasons have not been fully explored yet. This study is aimed to explore the effect of weather factors on increased number of hospitalization due to worsening of asthma symptoms. This will provide more information to the relevant authorities to allocate appropriate medical resources as per the weather conditions in Qingdao, China. Methods: All adult patients admitted for asthma exacerbation from 1 January, 2017 to 31 December, 2019 were enrolled from 13 main hospitals of Qingdao. The clinical data, including age, sex, smoking history, etc., were collected from the electronic medical record (EMR) systems. The hourly air quality of Qingdao from 2017-2019, including the air quality index (AQI), PM2.5 and PM10, was obtained from the China National Environmental Monitoring Centre. All these parameters during 2017-2019 were compared monthly. For meteorological data, the monthly horizontal wind at 850 hPa and vertical velocity at 500 hPa during 1960-2020 were obtained from National Center for Environmental Prediction (NCEP) and the National Center for Atmospheric Research (NCAR) global reanalysis dataset. The correlation analysis was applied to determine the association between asthma hospitalizations and the environmental factors, including atmospheric pressure, humidity, vertical visibility, and etc., monthly. Results: In all, 10,549 asthmatic inpatients (45.7% males, 54.3% females) were included in the study. The inpatients number for asthma exacerbation had a plateau lasting from March to June of 2019, accompanied with high PM2.5 and PM10, as well as bad air quality from January to March of 2019, potentially governed by the El Niño event in 2018. However, there was no significance correlation between the number of asthma hospitalizations and the average value of all environmental factors. Conclusions: The high rate of hospitalization for asthma exacerbation in Qingdao during the spring of 2019 was associated with the unfavorable weather conditions, which might be linked to the atmospheric circulation in East Asia.

The nephroprotective effects of Daucus carota and Eclipta prostrata against cisplatin-induced nephrotoxicity in rats.

The overuse of cisplatin (>50 mg/m2) is limited to nephrotoxicity, ototoxicity, gastrotoxicity, myelosuppression, and allergic reactions. The objective of this study was to investigate the nephroprotective effects of Daucus carota and Eclipta prostrata extracts on cisplatin-induced nephrotoxicity in Wistar albino rats. The study involved male Wistar albino rats of 8 weeks weighing 220-270 g. A single injection of 5 mg/kg was injected into the rats for nephrotoxicity. Rats were divided into four groups based on dose conentrations. Blood and urine samples of rats were collected on the 0, 7th, 14th, and 21st days for nephrological analysis. The results showed that Cis + DC/Cis + EP (600 mg/kg) significantly (p < 0.001) increased the body weight and reduced the kidney weight of cisplatin-induced nephrotoxicity in rats (p < 0.001) as compared to Cis group. The results showed that 600 mg/kg administration of Cis + DC/Cis +EP successfully (p < 0.005) improved the urine and plasmin creatinine, Na, and K level compared to the Cis group. Histopathological results confirmed that Cis + EP/Cis + DC effectively improved the renal abnormalities. It is concluded that the co-administration of Cis + EP extract showed exceptional nephroprotective effects at a dose rate of 600 mg/kg.

Dose Issues in Cancer Chemotherapy.

In this review, human methotrexate dosing regimens, as well as their relationship to data from in vitro cell culture and in vivo animal and human studies, are discussed. Low-dose, intermediate-dose, and high-dose therapies are covered. Since in vitro and in vivo screenings of potential cancer drugs are commonplace in the development of cancer chemotherapy, comparisons of the three criteria for effectiveness are important.

Hashimoto Encephalopathy as a Complication of Autoimmune Thyroiditis.

OBJECTIVE: To present a case of Hashimoto encephalopathy as a complication of autoimmune thyroiditis. CLINICAL PRESENTATION AND INTERVENTION: A previously healthy 56-year-old female presented with rapidly progressive cognitive decline and visual hallucinations. Being a diagnosis of exclusion, Hashimoto encephalopathy required an extensive laboratory and diagnostic workup, which was done over the course of a 15-day hospitalization. The patient recovered after initial treatment with intravenous methylprednisolone and was then switched to prednisone p.o. CONCLUSION: This case report illustrates the importance of awareness for Hashimoto encephalopathy, as it remains one of the few easily treatable and reversible causes of rapid cognitive decline.

Post-menopausal acquired diaphragmatic herniation in the context of endometriosis.

INTRODUCTION: Acquired diaphragmatic hernias are most commonly associated with traumatic thoracic injury and rarely heal spontaneously. Conditions that promote peritoneal seeding, such as endometriosis, are associated with spontaneous acquired diaphragmatic hernia formation. Non-traumatic acquired diaphragmatic herniation has previously been described in the context of catamenial pneumothorax, however post-menopausal endometriotic diaphragmatic herniation has not been previously reported. PRESENTATION OF CASE: A 57 year old post-menopausal female presented with a strangulated ischaemic loop of small bowel herniating through an acquired right sided endometriotic diaphragmatic hernia not previously visualised on imaging. Clamshell thoracolaparotomy was conducted and the necrotic section of small bowel was resected. The diaphragm was repaired and the patient recovered post-operatively without complications. DISCUSSION: This patient had a complete intestinal malrotation presenting acutely with a small bowel obstruction and herniation through an acquired diaphragmatic rupture. This was possibly related to a diaphragmatic defect caused by endometriosis. CONCLUSION: We presented a case of a post-menopausal acquired diaphragmatic herniation secondary to endometriosis; resulting in acute intestinal obstruction and bowel infarction. To our knowledge, such a case has not been previously reported in existing literature.

Rheumatoid Arthritis: A Brief Overview of the Treatment.

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disease, affecting the joints with varying severity among patients. The risk factors include age, gender, genetics, and environmental exposure (cigarette smoking, air pollutants, and occupational). Many complications can follow, such as permanent joint damage requiring arthroplasty, rheumatoid vasculitis, and Felty syndrome requiring splenectomy if it remains unaddressed. As there is no cure for RA, the treatment goals are to reduce the pain and stop/slow further damage. Here, we present a brief summary of various past and present treatment modalities to address the complications associated with RA.

Applications of nanoparticle systems in drug delivery technology.

The development of nanoparticle-based drug formulations has yielded the opportunities to address and treat challenging diseases. Nanoparticles vary in size but are generally ranging from 100 to 500 nm. Through the manipulation of size, surface characteristics and material used, the nanoparticles can be developed into smart systems, encasing therapeutic and imaging agents as well as bearing stealth property. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. This targeted and sustained drug delivery decreases the drug related toxicity and increase patient's compliance with less frequent dosing. Nanotechnology has proven beneficial in the treatment of cancer, AIDS and many other disease, also providing advancement in diagnostic testing.

Co-delivery strategies to overcome multidrug resistance in ovarian cancer.

Cancer is one of the leading causes of death and equally strikes both genders. Among women, ovarian cancer is responsible for many deaths as it remains symptomless in the earlier stages and generally diagnosed in third stage. At this point it becomes difficult to carry out de-bulking surgery and treatment with different chemotherapeutic drugs has shown resistance, a phenomenon known as multidrug resistance (MDR). Different treatment choices are available for ovarian cancer; however, this article only focuses on various co-delivery strategies, where two different agents are encapsulated in a single carrier and act via different pathways to overcome cancer cell resistance. Ovarian cancer develops MDR via different pathways but majorly involving pump and the non-pump mechanisms in most cases. To overcome MDR it is imperative to strike malignant cells from various directions. Nanocarriers are known to strike the pump mechanism by avoiding the drug efflux pump located on cellular membrane. The efflux pump can also be blocked by blocking activity of ATP binding cassette (ABC) membrane transporters. To stop the non-pump mechanism one can use chemosensitizers, genes, apoptotic factor and others. Treatment of cancer cells could even more effective if the drug is combined with co-agents in a single carrier with targeting moiety. These co-agents along with nanocarriers, allow the drug to accumulate in high enough concentrations in ovarian cancer cells to kill them without affecting normal cells.

Role of Transcription Factors in Steatohepatitis and Hypertension after Ethanol: The Epicenter of Metabolism.

Chronic alcohol consumption induces multi-organ damage, including alcoholic liver disease (ALD), pancreatitis and hypertension. Ethanol and ethanol metabolic products play a significant role in the manifestation of its toxicity. Ethanol metabolizes to acetaldehyde and produces reduced nicotinamide adenine dinucleotide (NADH) by cytosolic alcohol dehydrogenase. Ethanol metabolism mediated by cytochrome-P450 2E1 causes oxidative stress due to increased production of reactive oxygen species (ROS). Acetaldehyde, increased redox cellular state and ROS activate transcription factors, which in turn activate genes for lipid biosynthesis and offer protection of hepatocytes from alcohol toxicity. Sterol regulatory element binding proteins (SREBPs) and peroxisome proliferator activated-receptors (PPARs) are two key lipogenic transcription factors implicated in the development of fatty liver in alcoholic and non-alcoholic steatohepatitis. SREBP-1 is activated in the livers of chronic ethanol abusers. An increase in ROS activates nuclear factor erythroid-2-related factor-2 (Nrf2) and hypoxia inducible factor (HIF) to provide protection to hepatocytes from ethanol toxicity. Under ethanol exposure, due to increased gut permeability, there is release of gram-negative bacteria-derived lipopolysaccharide (LPS) from intestine causing activation of immune response. In addition, the metabolic product, acetaldehyde, modifies the proteins in hepatocyte, which become antigens inviting auto-immune response. LPS activates macrophages, especially the liver resident macrophages, Kupffer cells. These Kupffer cells and circulating macrophages secrete various cytokines. The level of tumor necrosis factor-α (TNFα), interleukin-1beta (IL-1ß), IL-6, IL-8 and IL-12 have been found elevated among chronic alcoholics. In addition to elevation of these cytokines, the peripheral iron (Fe(2+)) is also mobilized. An increased level of hepatic iron has been observed among alcoholics. Increased ROS, IL-1ß, acetaldehyde, and increased hepatic iron, all activate nuclear factor-kappa B (NF-κB) transcription factor. Resolution of increased reactive oxygen species requires increased expression of genes responsible for dismutation of increased ROS which is partially achieved by IL-6 mediated activation of signal transducers and activators of transcription 3 (STAT3). In addition to these transcription factors, activator protein-1 may also be activated in hepatocytes due to its association with resolution of increased ROS. These transcription factors are central to alcohol-mediated hepatotoxicity.

Neurocysticercosis: A case report and brief review.

Neurocysticercosis (NCC) is one of the seven neglected endemic zoonoses targeted by the World Health Organization. It is considered a common infection of the nervous system caused by the Taenia solium and is known to be the primary cause of preventable epilepsy in many developing countries. NCC is commonly resulted by the ingestion of Taenia solium eggs after consuming undercooked pork, or contaminated water. The parasite can grow in the brain and spinal cord within the nervous system, causing severe headache and seizures beside other pathological manifestations. Immigration and international travel to endemic countries has made this disease common in the United States. NCC can be diagnosed with computed tomography and magnetic resonance imaging of the brain. The treatment of the NCC including cysticidal drugs (e.g., albendazole and praziquantel), and neurosurgical procedure, depending upon the situation. A patient of Asian origin came to our clinic with complaints of dizziness, headaches and episodes seizures for the past twelve years without proper diagnosis. The computed tomography and magnetic resonance imaging scans indicated multilobulated cystic mass in the brain with the suspicion of neurocysticercosis.

Antiproliferative activity of the isoindigo 5'-Br in HL-60 cells is mediated by apoptosis, dysregulation of mitochondrial functions and arresting cell cycle at G0/G1 phase.

Our new compound, 5'-Br [(E)-1-(5'-bromo-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f]quinoline-8-carboxylic acid], had shown strong, selective antiproliferative activity against different cancer cell lines. Here, we aim to comprehensively characterize the mechanisms associated with its cytotoxicity in the human promyelocytic leukemia HL-60 cells. We focused at studying the involvement of apoptotic pathway and cell cycle effects. 5'-Br significantly inhibited proliferation by inducing caspase-dependent apoptosis. Involvement of caspase independent mechanism is also possible due to observed inability of z-VAD-FMK to rescue apoptotic cells. 5'-Br was found to trigger intrinsic apoptotic pathway as indicated by depolarization of the mitochondrial inner membrane, decreased level of cellular ATP, modulated expression and phosphorylation of Bcl-2 leading to loss of its association with Bax, and increased release of cytochrome c. 5'-Br treated cells were found arrested at G0/G1 phase with modulation in protein levels of cyclins, dependent kinases and their inhibitors. Expression and enzymatic activity of CDK2 and CDK4 was found inhibited. Retinoblastoma protein (Rb) phosphorylation was also inhibited whereas p21 protein levels were increased. These results suggest that the antiproliferative mechanisms of action of 5'-Br could involve apoptotic pathways, dysregulation of mitochondrial functions and disruption of cell cycle checkpoint.

Bioactive albumin-based carriers for tumour chemotherapy.

Proteins are posed as the natural counterpart of the synthetic polymers for the development of drug delivery systems and few of them, have been regarded safe for drug delivery purposes by the United States Food and Drug Administration (FDA). Serum albumin is the most abundant protein in human blood. Interest in the exploration of pharmaceutical applications of albumin-based drug delivery carriers, especially for the delivery of chemotherapeutic agents, has increased in recent years. Albumin has several advantages over synthetic polymers, as it is biocompatible, biodegradable, has low cytotoxicity and has an excellent binding capacity with various drugs. Micro- and nano-carriers not only protect active pharmaceutical ingredients against degradation, but also offer a prolonged release of drugs in a controlled fashion. Since existing tumour chemotherapeutic agents neither target tumour cells, nor are they specific to tumour cells, a slow release of drugs from carriers would be beneficial in targeting carcinogenic cells intracellularly. This article aims at providing an overview of pharmaceutical applications of albumin as a drug delivery carrier in tumour chemotherapy.

In vitro cytotoxicity of Artemisia vulgaris L. essential oil is mediated by a mitochondria-dependent apoptosis in HL-60 leukemic cell line.

BACKGROUND: The essential oil (EO) of Artemisia vulgaris L. has been traditionally used worldwide for treating a large number of diseases. Although major components in A. vulgaris EO have been shown to inhibit growth of different cancer cells, as pure compounds or part of other plants extracted oil, no information is known about its anti-proliferative activities. Therefore, the current investigation has evaluated the toxicity of the plant extracted oil from buds (AVO-b) and leaves (AVO-l) and characterized their growth inhibitory effects on cancer cells. METHODS: AVO-b and AVO-l from A. vulgaris L. were extracted by hydrodistillation, and their effect on the viability of human HL-60 promyelocytic leukemia and various other cancer cell lines was tested using MTT assay. Flow cytometric analysis of apoptosis, DNA fragmentation assay, caspases enzymatic activities and Western blotting were used to determine the apoptotic pathway triggered by their action on HL-60 cells. RESULTS: Low concentrations of AVO-b and AVO-l inhibited the growth of HL-60 cells in a dose- and time-dependent manner. Employing flow cytometric, DNA fragmentation and caspase activation analyses, demonstrated that the cytotoxic effect of the oils is mediated by a caspase-dependent apoptosis. Kinetic studies in the presence and absence specific caspase inhibitors showed that activation of caspase-8 was dependent and subsequent to the activation of caspases-9 and -3. In addition, the essential oil caused a disruption of the mitochondrial transmembrane potential (ΔΨm), increased the release of cytochrome c to the cytosol, and altered the expression of certain members of Bcl-2 family (Bcl-2, Bax and Bid), Apaf-1 and XIAP. Interestingly, low doses of AVO-b and AVO-1 also induced apoptosis in various cancer cell lines, but not in noncancerous cells. CONCLUSIONS: The results demonstrate that the EO-induced apoptosis in HL-60 cells is mediated by caspase-dependent pathways, involving caspases-3, -9, and -8, which are initiated by Bcl-2/Bax/Bid-dependent loss of ΔΨm leading to release of cytochrome c to the cytoplasm to activate the caspase cascade. The finding that AVO-b and AVO-l are more efficient to induce apoptosis in different cancer cell lines than noncancerous cells, suggests that A. vulgaris might be a promising source for new anticancer agents.

Is rapid withdrawal of anti-epileptic drug therapy during video EEG monitoring safe and efficacious?

PURPOSE: Video electroencephalographic monitoring (VEM) is used to record ictal and interictal epileptiform activity and to ascertain the level of concordance between the two. Often, taper or discontinuation of anti-epileptic (AED) therapy is needed to facilitate seizure occurrence. The safety of this practice is unclear and long-term sequelae have yet to be elucidated. METHODS: This is a prospective study of 158 patients subjected to combined sleep-deprived VEM with rapid AED withdrawal, for evaluation of seizure-like episodes over 24 months under the care of an epileptologist with direct nursing observation and EEG technician support in our telemetry unit. In most cases, AEDs were discontinued within 24h of admission. We assessed the diagnostic yield and safety of VEM as well as epilepsy surgery outcomes. RESULTS: VEM answered the study question in 90.5% of cases but failed to record ictal events in 9.5%. This diagnostic yield was achieved over a mean VEM duration of 4.53±1.44 days, with no benefit of longer monitoring. These findings improved quality of life by optimizing medical and surgical therapeutic planning, leading to improved seizure control. Overall, 32.9% of the cohort received epilepsy surgery. The complication rate was 5.06%, characterized largely by musculoskeletal pain secondary to clinical seizure activity, with no mortality observed. In the first month following VEM 2.5% of patients received emergency-room admission for seizure clustering. CONCLUSIONS: VEM with combined sleep deprivation and protocolized rapid AED withdrawal is a safe and effective investigative technique with no adverse long-term sequelae. It is a reliable strategy for therapeutic planning and can be used to determine candidacy for surgical treatment.

Formulation and evaluation of drug-loaded targeted magnetic microspheres for cancer therapy.

Enhanced and targeted drug delivery using biodegradable microspheres is emerging as a promising approach for cancer therapy. The main objective of the present research was to formulate, characterize, and evaluate iron oxide (magnetic) containing a bovine serum albumin-based microsphere drug delivery system, capable of efficiently delivering sulforaphane, a histone deacetylase inhibitor, for an extended period of time in vivo. Magnetic microspheres were prepared by spray-drying and characterized for their physicochemical properties and dissolution profile. Further, they were evaluated for therapeutic efficacy in in vitro and in vivo systems. In vitro studies in B16 melanoma cells revealed that there was about 13%-16% more inhibition of cell viability when either 30 µM or 50 µM of sulforaphane was used with iron oxide in the polymeric carrier. Data from in vivo studies in C57BL/6 mice revealed that the magnetic microspheres (localized to the tumor site with the help of a strong magnet) inhibited 18% more tumor growth as compared with sulforaphane in solution. In addition, there was a 40% reduction in histone deacetylation levels in mice treated with iron oxide microspheres containing sulforaphane. Thus, magnetic microspheres are shown to be an effective drug delivery system for anticancer drugs.

Formulation development of albumin based theragnostic nanoparticles as a potential delivery system for tumor targeting.

BACKGROUND: Generally, chemotherapeutic drugs attack on both normal and tumor cells non-specifically causing life threatening side effects, necessitating targeted drug delivery to tumors. PURPOSE: The purpose of this study is to formulate albumin-based nanoparticles for tumor targeted drug delivery and noninvasive diagnosis. METHODS: Albumin based nanoparticles (NPs) were developed as a potential tumor theragnostic agent by entrapping an anti cancer drug, doxorubicin and a near infrared dye, indocyanine green. Theragnostic nanoparticles were prepared using a well established coacervation/nanoprecipitation method followed by lyophilization. The formulation was optimized by varying process parameters using full factorial design of experiments. Release of dye and drug from NPs and physical state of the drug in NPs was studied using DSC. The NPs were injected into tumor bearing mice intravenously and imaged using a bio-imager. RESULTS: The optimized nanoparticle formulation had a particle size of 125.0 ± 1.8 nm, poly dispersity index of 0.180 ± 0.057 and zeta potential of -32.7 ± 0.9 mV. The release of dye and drug from the nanoparticles was determined to be quasi-fickian diffusion mediated. Differential scanning calorimetry (DSC) studies revealed the stability of drug in the NP. The in-vivo studies showed enhanced accumulation of the dye loaded NPs at the tumor site than the dye solution, thus allowing noninvasive tumor monitoring. CONCLUSION: These results project the newly proposed and evaluated nanoparticle formulation as a potential tumor targeting and imaging delivery system.

Effect of sulfhydryl modification on rat kidney basolateral plasma membrane transport function.

Transport processes are the hallmark of functioning kidney. Various nephrotoxicants disrupt the transport processes to manifest nephrotoxicity. Of several nephrotoxicants, mercuric chloride (HgCl(2)) depletes the reduced glutathione (GSH) in kidney and has been observed to affect the in vitro p-aminohippurate (PAH) transport by basolateral (BL) membrane vesicles. The role of renal nonprotein sulfhydryls such as, reduced GSH has been demonstrated to affect the PAH transport by BL membrane vesicles. The role of protein sulfhydryls in transport process of PAH by BL membrane is not known. Due to mercury mediated effects on sulfhydryls, the effects of protein-sulfhydryls (-SH) modifying reagents in the current study were investigated on PAH transport by BL membrane. It was observed that modification of -SH by p-chloromercuribenzoate sulphate (pCMBS), and mercuric chloride (HgCl(2)) decreased while recovering the protein -SH with dithiothreitol treatment provided protection against the effects of pCMBS, and HgCl(2) on PAH transport by BL membrane vesicles.

Self-assembling systems: mining a rich vein.

This paper summarizes a few of the self-assembling systems investigated in the authors' laboratory over the years. These include systems that mimic an enzyme, solubilize drugs, release encapsulated guests, assemble via hydrophobic surfaces, exhibit hysteresis in films, link cancer cells to vesicles, and destroy toxic compounds. Although the amphiphilic molecules are all rather different, one overriding theme predominates: just as the properties of molecules are not simple extrapolations from atoms, properties of self-assemblies are not simple extrapolations from molecules. Groups of molecules, properly assembled, can accomplish much more than an equal number of molecules functioning separately.