Advances in Gold Nanoparticles: Synthesis, Functionalization Strategies, and Theranostic Applications in Cancer.

Cancer is among the leading causes of mortality and morbidity in the world. Metallic nanoparticles, especially gold nanoparticles (AuNPs) have emerged to be attractive systems to circumvent the associated adverse effects. By the virtue of their unique properties of tunable size, shape, composition, optical properties, biocompatibility, minimal toxicity, multivalency, fluorescence-luminescence property and surface plasmon resonance; AuNPs have the potential to be used as drug delivery systems. It is vital to ensure that the drug reaches the target site of action for selective kill of cancer cells without harm to healthy cells. These AuNPs can be easily functionalized with a wide array of ligands like peptides, oligonucleotides, polymers, carbohydrates for active targeting to ensure site specific delivery and reduced systemic effects. AuNPs have been in-vestigated as carriers for gene delivery, drug delivery with or without photothermal therapy, in diagnosis based on radiation or spectroscopy. They have emerged as attractive theranostic approach in the overall management of cancer with superior benefit to risk features. In this review, we have discussed synthesis of different AuNPs (nanorods, spherical nanoparticles, and hollow AuNPs), their functionalization strategies and their applications in biomedical domain. Various research studies and clinical trials on application of AuNPs in diagnosis and therapeutics are highlighted.

The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.

Mitochondrial volume is maintained through the permeability of the inner mitochondrial membrane by a specific aquaporin and the osmotic balance between the mitochondrial matrix and cellular cytoplasm. Various electrolytes, such as calcium and hydrogen ions, potassium, and sodium, as well as other osmotic substances, affect the swelling of mitochondria. Intracellular glucose levels may also affect mitochondrial swelling, although the relationship between mitochondrial ion homeostasis and intracellular glucose is poorly understood. This article reviews what is currently known about how the Sodium-Glucose transporter (SGLT) may impact mitochondrial sodium (Na+) homeostasis. SGLTs regulate intracellular glucose and sodium levels and, therefore, interfere with mitochondrial ion homeostasis because mitochondrial Na+ is closely linked to cytoplasmic calcium and sodium dynamics. Recently, a large amount of data has been available on the effects of SGLT2 inhibitors on mitochondria in different cell types, including renal proximal tubule cells, endothelial cells, mesangial cells, podocytes, neuronal cells, and cardiac cells. The current evidence suggests that SGLT inhibitors (SGLTi) may affect mitochondrial dynamics regarding intracellular Sodium and hydrogen ions. Although the regulation of mitochondrial ion channels by SGLTs is still in its infancy, the evidence accumulated thus far of the effect of SGLTi on mitochondrial functions certainly will foster further research in this direction.

Knowledge and Perception Regarding Medication Error Among Nurses.

BACKGROUND: Patient safety is the major concern in providing quality care. Medication errors have been identified as the most common type of preventable errors. This study aimed to assess the knowledge and perception regarding medication error among nurses. METHODS: A quantitative cross-sectional research design was used. The study was conducted in four different private hospitals in Lalitpur. A total enumerative sampling technique was used to select 302 nurses from these hospitals. Descriptive statistical methods were used to assess socio-demographic variables and inferential statistics methods such as the chi-squared test was used to analyse the association between knowledge, perception, and its socio-demographic characteristics. RESULTS: Most of the respondents 244 (80.8%) agreed the cause of medication error occurs due to unclear handwriting and 217 (71.9%) agreed prescribing the wrong route or dose and time. Mostly respondents 126 (41.7%) had inadequate knowledge, 101 (33.4%) had adequate knowledge and 75 (24.8%) had moderate knowledge on medication error. Mostly respondents 273 (90.4%) had positive perception and 26 (8.6 %) had negative perception. CONCLUSIONS: Most of the nurses had inadequate knowledge but has positive perception on medication error. Appropriate strategies for reducing nurses' workload, barriers to reporting, and sensitization workshops in a regular basis by the administrator should be developed to address medication errors and enhance patient safety in hospital settings.

Alcoholic foamy degeneration: an unusual presentation of the alcoholic liver disease diagnosed on autopsy.

Alcoholic foamy degeneration (AFD) is an uncommon presentation of alcoholic liver disease (ALD) with characteristic histologic findings of foamy-looking hepatocytes due to the presence of abundant microvesicles of fat within the cytoplasm predominantly in perivenular and midzonal regions without inflammation and fibrosis. It is underdiagnosed as the patients quickly recover after alcoholic abstinence and are rarely caught on biopsies. AFD has better prognosis than alcoholic hepatitis, and the injury mechanism is different, warranting a different diagnosis. We present an uncommon case of AFD incidentally diagnosed during autopsy in a chronic alcoholic and diabetic man.

Biliary adenofibroma: a precursor lesion of intrahepatic cholangiocarcinoma.

Biliary adenofibroma (BAF) is an uncommon liver tumor with a high propensity for malignant transformation. The histomorphology of BAF with malignant transformation can show a spectrum of changes ranging from benign, dysplastic to frank malignancy. Thus, the diagnosis of BAF imposes the pursuit of dysplasia/ malignancy focus. We presented a case of intrahepatic cholangiocarcinoma arising from BAF in a 49-year-old woman with detailed histomorphology. We also performed a PubMed database search and tabulated all previously reported cases of BAF with dysplasia/ malignant transformation. A statistic comparison of age, sex ratio, size of the tumor, and survival following complete resection between BAFs with and without dysplasia/ malignancy from the retrieved data is presented. Our analysis did not highlight any statistically significant difference between BAFs with and without dysplasia/ malignancy in age, sex ratio, tumor size, and survival following complete surgical resection. Our study highlights the histopathology and immunohistochemistry of a case of BAF with malignant transformation and highlights the importance of this diagnosis in management. Further longitudinal studies on a larger cohort of patients are required to validate our findings.

Deoxyglucose-conjugated persistent luminescent nanoparticles for theragnostic application in fibrosarcoma tumor model.

Deoxyglucose conjugated nanoparticles with persistent luminescence have shown theragnostic potential. In this study, deoxyglucose-conjugated nano-particles with persistent luminescence properties were synthesized, and their theragnostic potential was evaluated in fibrosarcoma cancer cells and a tumor model. The uptake of nano-formulation was found to be higher in mouse fibrosarcoma (WEHI-164) cells cultured in a medium without glucose. Nanoparticles showed a higher killing ability for cancer cells compared to normal cells. A significant accumulation of nanoparticles to the tumor site in mice was evident by the increased tumor/normal leg ratio, resulting in a significant decrease in tumor volume and weight. Histopathological studies showed a significant decrease in the number of dividing mitotic cells but a greater number of apoptotic/necrotic cells in nanoparticle-treated tumor tissues, which was correlated with a lower magnitude of Ki-67 expression (a proliferation marker). Consequently, our results showed the potential of our nano-formulation for cancer theragnosis.

Biliary adenofibroma: a precursor lesion of intrahepatic cholangiocarcinoma

ABSTRACT Biliary adenofibroma (BAF) is an uncommon liver tumor with a high propensity for malignant transformation. The histomorphology of BAF with malignant transformation can show a spectrum of changes ranging from benign, dysplastic to frank malignancy. Thus, the diagnosis of BAF imposes the pursuit of dysplasia/ malignancy focus. We presented a case of intrahepatic cholangiocarcinoma arising from BAF in a 49-year-old woman with detailed histomorphology. We also performed a PubMed database search and tabulated all previously reported cases of BAF with dysplasia/ malignant transformation. A statistic comparison of age, sex ratio, size of the tumor, and survival following complete resection between BAFs with and without dysplasia/ malignancy from the retrieved data is presented. Our analysis did not highlight any statistically significant difference between BAFs with and without dysplasia/ malignancy in age, sex ratio, tumor size, and survival following complete surgical resection. Our study highlights the histopathology and immunohistochemistry of a case of BAF with malignant transformation and highlights the importance of this diagnosis in management. Further longitudinal studies on a larger cohort of patients are required to validate our findings.

Alcoholic foamy degeneration: an unusual presentation of the alcoholic liver disease diagnosed on autopsy

ABSTRACT Alcoholic foamy degeneration (AFD) is an uncommon presentation of alcoholic liver disease (ALD) with characteristic histologic findings of foamy-looking hepatocytes due to the presence of abundant microvesicles of fat within the cytoplasm predominantly in perivenular and midzonal regions without inflammation and fibrosis. It is underdiagnosed as the patients quickly recover after alcoholic abstinence and are rarely caught on biopsies. AFD has better prognosis than alcoholic hepatitis, and the injury mechanism is different, warranting a different diagnosis. We present an uncommon case of AFD incidentally diagnosed during autopsy in a chronic alcoholic and diabetic man.

Development of Core@Shell γ-Fe2O3@MnxOy@SiO2 Nanoparticles for Hyperthermia, Targeting, and Imaging Applications.

Monodispersed core@shell γ-Fe2O3@MnxOy nanoparticles have been prepared through thermolysis of iron and manganese oleate. Further, these prepared nanoparticles are coated with biocompatible substances such as silica and polyethylene glycol. These particles are highly biocompatible for different cell lines such as normal and cancer cell lines. The nanoparticles are used as hyperthermia agents, and successful hyperthermia treatment in cancer cells is carried out. As compared to γ-Fe2O3@SiO2, γ-Fe2O3@MnxOy@SiO2 shows the enhanced killing of cancer cells through hyperthermia. In order to make them potential candidates for targeting to cancer cells, folic acid (FA) is tagged to the nanoparticles. Fluorescein isothiocyanate (FITC) is also tagged onto these nanoparticles for imaging. The developed γ-Fe2O3@MnxOy@SiO2 nanoparticle can act as a single entity for therapy through AC magnetic field, imaging through FITC and targeting through folic acid simultaneously. This is the first report on this material, which is highly biocompatible for hyperthermia, imaging, and targeting.

Synthetic lethal kinases in Ras/p53 mutant squamous cell carcinoma.

The oncogene Ras and the tumor suppressor gene p53 are frequently co-mutated in human cancer and mutations in Ras and p53 can cooperate to generate a more malignant cell state. To discover novel druggable targets for cancers carrying co-mutations in Ras and p53, we performed arrayed, kinome focused siRNA and oncology drug phenotypic screening utilizing a set of syngeneic Ras mutant squamous cell carcinoma (SCC) cell lines that also carried co-mutations in selected p53 pathway genes. These cell lines were derived from SCCs from carcinogen-treated inbred mice which harbored germline deletions or mutations in Trp53, p19Arf, Atm, or Prkdc. Both siRNA and drug phenotypic screening converge to implicate the phosphoinositol kinases, receptor tyrosine kinases, MAP kinases, as well as cell cycle and DNA damage response genes as targetable dependencies in SCC. Differences in functional kinome profiles between Ras mutant cell lines reflect incomplete penetrance of Ras synthetic lethal kinases and indicate that co-mutations cause a rewiring of survival pathways in Ras mutant tumors. This study describes the functional kinomic landscape of Ras/p53 mutant chemically-induced squamous cell carcinoma in both the baseline unperturbed state and following DNA damage and nominates candidate therapeutic targets, including the Nek4 kinase, for further development.

How Common are Depressive-Anxiety States, Body Image Concerns and Low Self-Esteem in Patients of PCOS?

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age with increased incidence of emotional disturbances and other psychopathology. We undertook this research to study the prevalence and severity of depression and anxiety as well as understand body image disturbances and self-esteem of the women of PCOS. We studied the relationship of depressive symptoms with self-esteem and body image disturbances. METHOD: A total of 105 patients diagnosed as PCOS were recruited from gynecology OPD after informed consent and ethics approval. A proforma along with Beck's Depression Inventory, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Body Image Concern Inventory and Rosenberg' s Self-Esteem Scale were administered to patients for further assessment. RESULTS: In total, 54 (51.43%) patients of PCOS had depression on BDI, 12( 11.43%) patients had body image disturbances an d 23 (21.90%) patients had a low self-esteem. A total of 21 patients( 20%) had mild and moderate depression while 5% had severe depression. Majority 53 (50.48%) of our patients had mild anxiety whereas severe to extreme anxiety was seen in about 31% of patients. Body image disturbances were seen in only 12(11.43%) patients and low self-esteem was present in 23 patients. No statistically significant correlation of depression was seen with body image or self-esteem. CONCLUSIONS: The results of this study indicate that there is a high prevalence of depression and anxiety in patients of PCOS than body image concerns and low self-esteem. Prognosis for patients would improve by liaison between gynecologist and psychiatrist.

DNA ligase IV mutations confer shorter lifespan and increased sensitivity to nutrient stress in Drosophila melanogaster.

The nonhomologous end-joining pathway is a primary DNA double-strand break repair pathway in eukaryotes. DNA ligase IV (Lig4) catalyzes the final step of DNA end ligation in this pathway. Partial loss of Lig4 in mammals causes Lig4 syndrome, while complete loss is embryonically lethal. DNA ligase 4 (DNAlig4) null Drosophila melanogaster is viable, but sensitive to ionizing radiation during early development. We proposed to explore if DNAlig4 loss induced other long-term sensitivities and defects in D. melanogaster. We demonstrated that DNAlig4 mutant strains had decreased lifespan and lower resistance to nutrient deprivation, indicating Lig4 is required for maintaining health and longevity in D. melanogaster.

Brilliant Nonlinear Optical Response of Ho3+ and Yb3+ Activated YVO4 Nanophosphor and Its Conjugation with Fe3O4 for Smart Anticounterfeit and Hyperthermia Applications.

YVO4:Ho3+/Yb3+ nanophosphors prepared by an effective polyol-mediated route show dual-mode behavior in photoluminescence. Upon 980 nm excitation, the upconversion red emission spectrum exhibits a bright red peak at ∼650 nm, characteristic of the electronic transition of the Ho3+ ion via involvement of two-photon absorption, which has been confirmed by the power-dependent luminescence study. Moreover, at 300 nm excitation, downconversion emission peaks are observed at 550, 650, and ∼755 nm. The nonradiative resonant energy transfer occurs from the V-O charge transfer band to Ho3+ ions, resulting in an improved emission of Ho3+ ions. Moreover, polyethylene glycol-coated nanoparticles make it suitable for water dispersibility; and these particles are conjugated with Fe3O4 nanoparticles to form magnetic-luminescent hybrid nanoparticles. Highly water-dispersible magnetic-luminescent hybrid material attained the hyperthermia temperature (∼42 °C) under an applied AC magnetic field. The specific absorption rate value is found to be high (138 W/g), which is more than that of pure superparamagnetic Fe3O4 nanoparticles. At 300 nm excitation, the high quantum yield value of ∼27% is obtained from YVO4:Ho3+/Yb3+, which suggests that it is a good phosphor material. By employing the neutron activation analysis technique, it is shown that nanophosphor particles can absorb Au3+ up to the ppm level. Interestingly, such nanophosphor also shows the potentiality for anticounterfeiting applications.

Super Bright Red Upconversion in NaErF4:0.5%Tm@NaYF4:20%Yb Nanoparticles for Anti-counterfeit and Bioimaging Applications.

Nanocrystals having single-band red emission under near-infrared (NIR) excitation through the upconversion process offer great advantages in terms of enhanced cellular imaging in in vitro and in vivo experiments in the biological window (600-900 nm), as a security ink, in photothermal therapy (PTT), in photodynamic therapy (PDT), and so forth but are challenging for materials scientists. In this work, we report for the first time the preparation of a super bright red emitter at 655 nm from monodispersed NaErF4:0.5%Tm@NaYF4:20%Yb nanocrystals (core@active shell). This phosphor exhibits 35 times stronger photoluminescence as compared to NaErF4:0.5%Tm@NaYF4 (core@inactive shell). Here, an Er3+-enriched host matrix works simultaneously as an activator and a sensitizer under NIR excitation. Upconversion red emission at 655 nm arises due to the electronic transition of Er3+ via the involvement of a three-photon absorption (expected to be a two-photon absorption), which has been confirmed via a power-dependent luminescence study. Tm3+ ions incorporated into the core with the active shell act as trapping centers, which promote the red band emission via the back-energy transfer process. Moreover, the active shell containing Yb3+ ions efficiently transfers the energy to the Er3+-enriched core, which suppresses the nonradiative channel rate, and Tm3+ ions act as trapping centers, which reduce the luminescence quenching via reduction of energy migration to the surface of the host lattice. Also, we have shown the potential applications of these nanocrystals: cellular imaging through downconversion and upconversion processes and security ink.

DNA Ligase IV Prevents Replication Fork Stalling and Promotes Cellular Proliferation in Triple Negative Breast Cancer.

DNA damage is a hallmark of cancer, and mutation and misregulation of proteins that maintain genomic fidelity are associated with the development of multiple cancers. DNA double strand breaks are arguably considered the most deleterious type of DNA damage. The nonhomologous end-joining (NHEJ) pathway is one mechanism to repair DNA double strand breaks, and proteins involved in NHEJ may also regulate DNA replication. We previously established that DNA-PKcs, a NHEJ protein, promotes genomic stability and cell viability following cellular exposure to replication stress; we wanted to discern whether another NHEJ protein, DNA ligase IV (Lig4), shares this phenotype. Our investigations focused on triple negative breast cancer cells, as, compared to nonbasal breast cancer, LIG4 is frequently amplified, and an increased gene dose is associated with higher Lig4 expression. We depleted Lig4 using siRNA and confirmed our knockdown by qPCR and western blotting. Cell survival diminished with Lig4 depletion alone, and this was associated with increased replication fork stalling. Checkpoint protein Chk1 activation and dephosphorylation were unchanged in Lig4-depleted cells. Lig4 depletion resulted in sustained DNA-PKcs phosphorylation following hydroxyurea exposure. Understanding the effect of Lig4 on genomic replication and the replication stress response will clarify the biological ramifications of inhibiting Lig4 activity. In addition, Lig4 is an attractive clinical target for directing CRISPR/Cas9-mediated repair towards homology-directed repair and away from NHEJ, thus understanding of how diminishing Lig4 impacts cell biology is critical.