Functional fluorescent nanomaterials for the detection, diagnosis and control of bacterial infection and biofilm formation: Insight towards mechanistic aspects and advanced applications.

Infectious diseases resulting from the high pathogenic potential of several bacteria possesses a major threat to human health and safety. Traditional methods used for screening of these microorganisms face major issues with respect to detection time, selectivity and specificity which may delay treatment for critically ill patients past the optimal time. Thus, a convincing and essential need exists to upgrade the existing methodologies for the fast detection of bacteria. In this context, increasing number of newly emerging nanomaterials (NMs) have been discovered for their effective use and applications in the area of diagnosis in bacterial infections. Recently, functional fluorescent nanomaterials (FNMs) are extensively explored in the field of biomedical research, particularly in developing new diagnostic tools, nanosensors, specific imaging modalities and targeted drug delivery systems for bacterial infection. It is interesting to note that organic fluorophores and fluorescent proteins have played vital role for imaging and sensing technologies for long, however, off lately fluorescent nanomaterials are increasingly replacing these due to the latter's unprecedented fluorescence brightness, stability in the biological environment, high quantum yield along with high sensitivity due to enhanced surface property etc. Again, taking advantage of their photo-excitation property, these can also be used for either photothermal and photodynamic therapy to eradicate bacterial infection and biofilm formation. Here, in this review, we have paid particular attention on summarizing literature reports on FNMs which includes studies detailing fluorescence-based bacterial detection methodologies, antibacterial and antibiofilm applications of the same. It is expected that the present review will attract the attention of the researchers working in this field to develop new engineered FNMs for the comprehensive diagnosis and treatment of bacterial infection and biofilm formation.

A review on nanotechnological perspective of "the amyloid cascade hypothesis" for neurodegenerative diseases.

Neurodegenerative diseases (NDs) are characterized by progressive degeneration of neurons which deteriorates the brain functions. An early detection of the onset of NDs is utmost important, as it will provide the fast treatment strategies to prevent further progression of the disease. Conventionally, accurate diagnosis of the brain related disorders is difficult in their early phase. To solve this problem, nanotechnology based neurofunctional imaging and biomarker detection techniques have been developed which allows high specificity and sensitivity towards screening and diagnosis of NDs. Another challenge to treat the brain related disorders is to overcome the complex integrity of blood-brain-barrier (BBB) for the delivery of theranostic agents. Fortunately, utilization of nanomaterials has been pursued as promising strategy to address this challenge. Herein, we critically highlighted the recent improvements in the field of neurodiagnostic and therapeutic approaches involving innovative strategies for diagnosis, and inhibition of protein aggregates. We have provided particular emphasis on the use of nanotechnology which can push forward the blooming research growth in this field to win the battle against devastating NDs.

Single-walled carbon nanotube conjugated cytochrome c as exogenous nano catalytic medicine to combat intracellular oxidative stress.

Mitochondrial dysfunction has been reported to be one of the main causes of many diseases including cancer, type2 diabetes, neurodegenerative disorders, cardiac ischemia, sepsis, muscular dystrophy, etc. Under in vitro conditions, Cytochrome C (Cyt C) maintains mitochondrial homeostasis and stimulates apoptosis, along with being a key participant in the life-supporting function of ATP synthesis. Hence, the medicinal importance of Cyt C as catalytic defense is immensely important in various mitochondrial disorders. Here, we have developed a nanomaterial via electrostatically conjugating oxidized single-wall carbon nanotube with Cyt C (Cyt C@cSWCNT) for the exogenous delivery of Cyt C. The chemical and morphological characterization of the developed Cyt C@cSWCNT was done using UV-vis, FTIR, XPS, powder XRD, TGA/DSC, TEM, etc. The developed Cyt C@cSWCNT exhibited bifunctional catalase and peroxidase activity with Km (∼ 642.7 µM and 351.6 µM) and Vmax (∼0.33 µM/s and 2.62 µM/s) values, respectively. Also, through this conjugation Cyt C was found to retain its catalytic activity even at 60 °C, excellent catalytic recyclability (at least up to 3 times), and wider pH activity (pH = 3 to 9). Cyt C@cSWCNT was found to promote intracellular ROS quenching and maintain mitochondrial membrane potential and cellular membrane integrity via Na+/K+ ion homeostasis during the H2O2 stress. Overall the present strategy provides an alternative approach for the exogenous delivery of Cyt C which can be used as nano catalytic medicine.

Rare Cause of CSOM: Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is a proliferation of dendritic mononuclear cells with infiltration into organs locally or diffusely. Most cases occur in children. LCH can also present as chronic otitis media and otitis externa due to involvement of the mastoid and petrous portions of the temporal bone with partial obstruction of the auditory canal. A 4 year old male child presented with complaints of bilateral ear discharge for 4 months and inability to walk and giddiness for 2 days. On otoscopic examination, in right ear, polypoidal tissue was present in the external auditory canal which bled on touch. CECT head and MRI brain was done which showed large altered intensities in the region of bilateral external and middle ears involving the temporal bone. It also showed a well defined ovoid expansile lesion involving the skull vault in left high parietal region. Biopsy was taken from the polypoidal tissue in the right EAC which on HPE showed features suspicious for LCH. On IHC, the tissue was found out to be immunoreactive for CD 68, CD 1a and S-100 with score of 4+ for all three of the IHC markers. Patient was later put on chemotherapy and steroids which resulted in disease remission.

Bioinspired Metal-Free Fluorescent Carbon Nanozyme with Dual Catalytic Activity to Confront Cellular Oxidative Damage.

Development of metal-free, recyclable enzyme mimics is challenging and requires key chemical modifications at the molecular level. Here, nitrilotriacetic acid-functionalized carbon nanospheres (LC-CNS@NTA) were prepared from the nitrogen-rich weed Lantana camara (LC) using a simple hydrothermal reaction condition. Transmission electron microscopy (TEM) studies revealed size of ∼160 ± 20 nm for LC-CNS@NTA whereas, the same showed fluorescence emission at ∼520 nm with a ∼63% quantum yield. Furthermore, LC-CNS@NTA showed strong peroxidase (Pxrd) activity toward a wide range of substrate viz., H2O2, 3,3',5,5'-tetramethylbenzidine, and o-phenylenediamine with Km and Vmax values of ∼257 µM and 1.06 µM/s, 282 µM and 1.47 µM/s, and 270.8 µM and 1.647 µM/s, respectively. Interestingly, this also showed catalase (CAT) activity against H2O2 with Km and Vmax values of ∼0.374 µM and 1.87 µM/s, respectively. It was observed that LC-CNS@NTA could effectively reduce the oxidative stress-induced cytotoxicity of HEK293 cells via retention of mitochondrial membrane potential, prevention of lipid peroxidation and DNA damage. It was further found that LC-CNS@NTA-treated cells showed reduced level of intracellular protein carbonylation and protein aggregation. The finding of the present study is expected to pave the path for designing engineered metal-free carbon nanozyme with dual enzyme mimic activity.

Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis.

PURPOSE: While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known. EXPERIMENTAL DESIGN: PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor. RESULTS: Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24-0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10-0.31) and HER2+ (HR = 0.32; 95% PI, 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19-0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27-0.54), with no significant difference between the two groups (P = 0.60). CONCLUSIONS: Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2+ breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response.See related commentary by Esserman, p. 2771.

Role of diffusion-weighted MRI in differentiating benign from malignant bone tumors.

OBJECTIVE: To evaluate the role of diffusion-weighted MRI in differentiating benign from malignant primary bone tumors. To know the sensitivity and specificity of diffusion weighted MRI and calculating apparent diffusion coefficient (ADC) cutoff in differentiating benign from malignant primary bone tumors. METHODS AND MATERIALS: This is a prospective observational study of 50 patients, who were clinically or radiologically suspected with primary bone tumor and referred to the Department of Radiodiagnosis, for radiography or for MRI. These patients underwent routine MRI sequences including diffusion-weighted MRI with b-values of 0, 500 and 1000, followed by pathological examination supplemented by immunohistochemistry (wherever necessary). Hematological malignancies, recently biopsied cases and recurrent cases were excluded from the study. RESULTS: Out of 50 patients with suspected bone tumors, 15 were benign (and tumor like lesions) and 35 were malignant primary bone tumors. The most common age group involved for both benign and malignant primary bone tumors was 11-20 years (23 cases-46%). In our study, total number of affected males were 27 (54%) and total number of affected females were 23 (46%) with M:F ratio of 1.17:1. In this study 72% lesions had appendicular bone involvement and 28% had axial bone involvement. 94.3% of malignant lesions showed restriction on diffusion-weighted imaging (DWI) and in 80 % of benign lesions restriction was absent on DWI which was statistically significant. Mean ADC levels in malignant lesions was 1.092 ± 0.497 and in benign lesions was 1.62 ± 0.596 which was statistically significant. Chondrosarcoma had highest ADC and Ewing's sarcoma had lowest ADC values in malignant lesions. Chondroblastoma had highest ADC and Osteomyelitis had lowest ADC values in benign lesions. ADC value of 1.31 had highest sensitivity and specificity to differentiate between benign and malignant lesions. CONCLUSION: DWI is helpful in differentiating malignant from benign bone tumors and tumor like lesions with diffusion restriction favoring malignancy. Inspite of some overlap, ADC values of benign and malignant bone tumors are different and measurement of ADC values improves the accuracy of the diagnosis of bone tumors and tumor like lesions. Calculation of ADC may also be used as baseline reference to assess response to treatment in future or for follow up. ADVANCES IN KNOWLEDGE: DWI imaging (and ADC values) has been extensively used in neuroimaging. Extension of this application to musculoskeletal-oncologic imaging is not so well studied. Apart from differentiating benign from malignant lesions which is the main focus of this study, assessment of response to treatment by ADC values may be possible in near future.

Engineered Bright Blue- and Red-Emitting Carbon Dots Facilitate Synchronous Imaging and Inhibition of Bacterial and Cancer Cell Progression via 1O2-Mediated DNA Damage under Photoirradiation.

The development of biocompatible, widely applicable fluorescent imaging probe, with emission beyond the cellular and tissue autofluorescence interference, is a challenging task. In this regard, a series of 28 different fluorescent carbon dots (CDs) were synthesized using carbohydrates as carbon and cysteine (Cys) and o-phenylenediamine (OPD) as nitrogen source. The screened CDs showed photostability with bright blue (∼505-520 nm) and red (∼588-596 nm) emission and high fluorescence quantum yield (QY = 72.5 ± 4.5%). FTIR and NMR studies suggested presence of carboxylate and ester group for Cys- and OPD-based CDs, respectively. HRTEM results showed particle size of ∼3.3-5.8 nm for all the developed CDs. The antibacterial studies suggested that the developed CDs showed preferential antibacterial activity against Escherichia coli, with IC50 value of ∼200 µg/mL. Cytotoxicity and confocal microscopy studies of HeLa cells reflected that these CDs showed both anticancer activity and imaging ability. Agarose gel electrophoresis, together with SOSG assay and thiol estimation studies, suggested oxidative stress induced DNA degradation to be the primary cause for cell death. These hemocompatible CDs can thus be used as simultaneous imaging probe and photo dynamic therapeutic agent for both antibacterial and anticancer activity.

Toxicity Concerns of Therapeutic Nanomaterials.

In the modern era, research on the synthesis of nanoparticles (NPs) has been growing exponentially. Due to their small size together with extra-ordinary physico-chemical properties, a variety of NPs i.e., metallic, carbon-based, fluorescent, and polymer-based have been exploited in different fields such as tissue engineering, drug delivery, and various other therapeutic applications. Instead of multi-disciplinary applications of NPs, research dealing with the toxicity concerns and influence of such materials, on the public health, plants and environment is still in its infancy. NPs can cause damage at the cellular, sub-cellular, molecular and protein levels owing to their extremely small size, large surface area to volume ratio, shape, and surface functionality. The present review is aimed to provide wide-ranging information related to NPs toxicology, the mechanisms of action, routes of their entry into the body and probable impacts on human health. Understanding of NPs entry routes into the body entails further research so as to update policymakers and regulatory bodies about the toxicity concerns associated with these nanomaterials. Proper characterization of NPs, factors affecting uptake and toxicity of NPs, as well as an understanding of processes when NPs come in contact with living beings, is critical to estimate the possible hazards.