A Path of Novelty from Nanoparticles to Nanobots: Theragnostic Approach for Targeting Cancer Therapy.

Pharmaceutical development of cancer therapeutics is a dynamic area of research. Even after decades of intensive work, cancer continues to be a dreadful disease with an ever-increasing global incidence. The progress of nanotechnology in cancer research has overcome inherent limitations in conventional cancer chemotherapy and fulfilled the need for target-specific drug carriers. Nanotechnology uses the altered patho-physiological microenvironment of malignant cells and offers various advantages like improved solubility, reduced toxicity, prolonged drug circulation with controlled release, circumventing multidrug resistance, and enhanced biodistribution. Early cancer detection has a crucial role in selecting the best drug regime, thus, diagnosis and therapeutics go hand in hand. Furthermore, nanobots are an amazing possibility and promising innovation with numerous significant applications, particularly in fighting cancer and cleaning out blood vessels. Nanobots are tiny robots, ranging in size from 1 to 100 nm. Moreover, the nanobots would work similarly to white blood cells, watching the bloodstream and searching for indications of distress. This review articulates the evolution of various organic and inorganic nanoparticles and nanobots used as therapeutics, along with their pros and cons. It also highlights the shift in diagnostics from conventional methods to more advanced techniques. This rapidly growing domain is providing more space for engineering desired nanoparticles that can show miraculous results in therapeutic and diagnostic trials.

Surface Modification Strategies for Chrysin-Loaded Iron Oxide Nanoparticles to Boost Their Anti-Tumor Efficacy in Human Colon Carcinoma Cells.

Enhancing nanoparticles' anti-cancer capabilities as drug carriers requires the careful adjustment of formulation parameters, including loading efficiency, drug/carrier ratio, and synthesis method. Small adjustments to these parameters can significantly influence the drug-loading efficiency of nanoparticles. Our study explored how chitosan and polyethylene glycol (PEG) coatings affect the structural properties, drug-loading efficiency, and anti-cancer efficacy of Fe3O4 nanoparticles (NPs). The loading efficiency of the NPs was determined using FTIR spectrometry and XRD. The quantity of chrysin incorporated into the coated NPs was examined using UV-Vis spectrometry. The effect of the NPs on cell viability and apoptosis was determined by employing the HCT 116 human colon carcinoma cell line. We showed that a two-fold increase in drug concentration did not impact the loading efficiency of Fe3O4 NPs coated with PEG. However, there was a 33 Å difference in the crystallite sizes obtained from chitosan-coated Fe3O4 NPs and drug concentrations of 1:0.5 and 1:2, resulting in decreased system stability. In conclusion, PEG coating exhibited a higher loading efficiency of Fe3O4 NPs compared to chitosan, resulting in enhanced anti-tumor effects. Furthermore, variations in the loaded amount of chrysin did not impact the crystallinity of PEG-coated NPs, emphasizing the stability and regularity of the system.

SPIONs Conjugate Supported Anticancer Drug Doxorubicin's Delivery: Current Status, Challenges, and Prospects.

Considerable efforts have been directed towards development of nano-structured carriers to overcome the limitations of anticancer drug, doxorubicin's, delivery to various cancer sites. The drug's severe toxicity to cardio and hepatic systems, low therapeutic outcomes, inappropriate dose-demands, metastatic and general resistance, together with non-selectivity of the drug have led to the development of superparamagnetic iron oxide nanoparticles (SPIONs)-based drug delivery modules. Nano-scale polymeric co-encapsulation of the drug, doxorubicin, with SPIONs, the SPIONs surface end-groups' cappings with small molecular entities, as well as structural modifications of the SPIONs' surface-located functional end-groups, to attach the doxorubicin, have been achieved through chemical bonding by conjugation and cross-linking of natural and synthetic polymers, attachments of SPIONs made directly to the non-polymeric entities, and attachments made through mediation of molecular-spacer as well as non-spacer mediated attachments of several types of chemical entities, together with the physico-chemical bondings of the moieties, e.g., peptides, proteins, antibodies, antigens, aptamers, glycoproteins, and enzymes, etc. to the SPIONs which are capable of targeting multiple kinds of cancerous sites, have provided stable and functional SPIONs-based nano-carriers suitable for the systemic, and in vitro deliveries, together with being suitable for other biomedical/biotechnical applications. Together with the SPIONs inherent properties, and ability to respond to magnetic resonance, fluorescence-directed, dual-module, and molecular-level tumor imaging; as well as multi-modular cancer cell targeting; magnetic-field-inducible drug-elution capacity, and the SPIONs' magnetometry-led feasibility to reach cancer action sites have made sensing, imaging, and drug and other payloads deliveries to cancerous sites for cancer treatment a viable option. Innovations in the preparation of SPIONs-based delivery modules, as biocompatible carriers; development of delivery route modalities; approaches to enhancing their drug delivery-cum-bioavailability have explicitly established the SPIONs' versatility for oncological theranostics and imaging. The current review outlines the development of various SPIONs-based nano-carriers for targeted doxorubicin delivery to different cancer sites through multiple methods, modalities, and materials, wherein high-potential nano-structured platforms have been conceptualized, developed, and tested for, both, in vivo and in vitro conditions. The current state of the knowledge in this arena have provided definite dose-control, site-specificity, stability, transport feasibility, and effective onsite drug de-loading, however, with certain limitations, and these shortcomings have opened the field for further advancements by identifying the bottlenecks, suggestive and plausible remediation, as well as more clear directions for future development.

Nuclear incorporation of iron during the eukaryotic cell cycle.

Scanning X-ray fluorescence microscopy has been used to probe the distribution of S, P and Fe within cell nuclei. Nuclei, which may have originated at different phases of the cell cycle, are found to show very different levels of Fe present with a strongly inhomogeneous distribution. P and S signals, presumably from DNA and associated nucleosomes, are high and relatively uniform across all the nuclei; these agree with X-ray phase contrast projection microscopy images of the same samples. Possible reasons for the Fe incorporation are discussed.

The use of DAPI fluorescence lifetime imaging for investigating chromatin condensation in human chromosomes.

Chromatin undergoes dramatic condensation and decondensation as cells transition between the different phases of the cell cycle. The organization of chromatin in chromosomes is still one of the key challenges in structural biology. Fluorescence lifetime imaging (FLIM), a technique which utilizes a fluorophore's fluorescence lifetime to probe changes in its environment, was used to investigate variations in chromatin compaction in fixed human chromosomes. Fixed human metaphase and interphase chromosomes were labeled with the DNA minor groove binder, DAPI, followed by measurement and imaging of the fluorescence lifetime using multiphoton excitation. DAPI lifetime variations in metaphase chromosome spreads allowed mapping of the differentially compacted regions of chromatin along the length of the chromosomes. The heteromorphic regions of chromosomes 1, 9, 15, 16, and Y, which consist of highly condensed constitutive heterochromatin, showed statistically significant shorter DAPI lifetime values than the rest of the chromosomes. Differences in the DAPI lifetimes for the heteromorphic regions suggest differences in the structures of these regions. DAPI lifetime variations across interphase nuclei showed variation in chromatin compaction in interphase and the formation of chromosome territories. The successful probing of differences in chromatin compaction suggests that FLIM has enormous potential for application in structural and diagnostic studies.

Epidemiological patterns of cervical human papillomavirus infection among women presenting for cervical cancer screening in North-Eastern Nigeria.

BACKGROUND: Sub-Saharan countries including Nigeria have the highest burden of Human Papillomavirus (HPV) infection in the world. Most studies on HPV surveillance in Nigeria were done in the southern part of the country. Geographical and socio-cultural diversity of Nigeria makes these data unlikely to be universally representative for the entire country. Northern Nigeria especially the North-East carries a higher prevalence of cervical cancer and many of its risk factors. The region may be harbouring a higher prevalence of HPV infection with a possibility of different genotypic distribution. This study was carried out to determine the burden and confirm the predominant HPV genotypes among women presenting for cervical cancer screening at the Federal Teaching Hospital Gombe (FTHG), North-eastern, Nigeria. METHODS: The study was an observational hospital based cross sectional study among women who presented for cervical cancer screening in FTHG. A total of 209 consenting women were tested for cervical HPV infection using PCR. DNA sequencing was carried out on positive samples to determine the prevalent HPV genotypes. RESULTS: The prevalence of cervical HPV infection among the participants with mean age of 39.6 ± 10.4 years was 48.1 %. The five most predominant genotypes were 18, 16, 33, 31 and 35, with prevalence of 44.7 %, 13.2 %, 7.9 %, 5.3 % and 5.3 % respectively. Other genotypes observed were 38, 45, 56, 58, 82 and KC5. Multiple HPV infections were detected among 7.9 % of participants. Risk factors such as level of education (X (2) = 15.897; p = 0.007), age at sexual debut (X (2) = 6.916; p = 0.009), parity (X (2) = 23.767; p = 0.000), number of life time sexual partners (X (2) = 7.805; p = 0.005), age at first pregnancy (X (2) = 10.554; p = 0.005) and history of other malignancies (X (2) = 7.325; p = 0.007) were found to have a statistically significant association with HPV infection. CONCLUSION: This study identified a high burden of HPV infection in Northern Nigeria while also confirming HPV 18 and 16 as the most predominant genotypes. It further justifies the potential benefit of the currently available HPV vaccines in the area. A larger and community based study is however recommended for better representation of the area.

Endoscopic cystogastrostomy: minimally invasive approach for pancreatic pseudocyst.

Pancreatic pseudocysts in children are not uncommon. Non-resolving pseudocysts often require surgical intervention. Endoscopic cystogastrostomy is a minimally invasive procedure which is recommended for this condition. We report a large pancreatic pseudocyst in a 4-year old child, which developed following therapy with PEG-Asparaginase for acute lymphoblastic leukemia. It was managed with minimally invasive procedure.

Comprehensive cytogenomic profile of the in vitro neuronal model SH-SY5Y.

The widely studied SH-SY5Y human neuroblastoma cell line provides a classic example of how a cancer cell line can be instrumental for discoveries of broad biological and clinical significance. An important feature of the SH-SY5Y cells is their ability to differentiate into a functionally mature neuronal phenotype. This property has conferred them the potential to be used as an in vitro model for studies of neurodegenerative and neurodevelopmental disorders. Here, we present a comprehensive assessment of the SH-SY5Y cytogenomic profile. Our results advocate for molecular cytogenetic data to inform the use of cancer cell lines in research.

Functional human artificial chromosomes are generated and stably maintained in human embryonic stem cells.

We present a novel and efficient non-integrating gene expression system in human embryonic stem cells (hESc) utilizing human artificial chromosomes (HAC), which behave as autonomous endogenous host chromosomes and segregate correctly during cell division. HAC are important vectors for investigating the organization and structure of the kinetochore, and gene complementation. HAC have so far been obtained in immortalized or tumour-derived cell lines, but never in stem cells, thus limiting their potential therapeutic application. In this work, we modified the herpes simplex virus type 1 amplicon system for efficient transfer of HAC DNA into two hESc. The deriving stable clones generated green fluorescent protein gene-expressing HAC at high frequency, which were stably maintained without selection for 3 months. Importantly, no integration of the HAC DNA was observed in the hESc lines, compared with the fibrosarcoma-derived control cells, where the exogenous DNA frequently integrated in the host genome. The hESc retained pluripotency, differentiation and teratoma formation capabilities. This is the first report of successfully generating gene expressing de novo HAC in hESc, and is a significant step towards the genetic manipulation of stem cells and potential therapeutic applications.

Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by mutations in the Krebs cycle enzyme fumarate hydratase (FH). It has been proposed that "pseudohypoxic" stabilization of hypoxia-inducible factor-α (HIF-α) by fumarate accumulation contributes to tumorigenesis in HLRCC. We hypothesized that an additional direct consequence of FH deficiency is the establishment of a biosynthetic milieu. To investigate this hypothesis, we isolated primary mouse embryonic fibroblast (MEF) lines from Fh1-deficient mice. As predicted, these MEFs upregulated Hif-1α and HIF target genes directly as a result of FH deficiency. In addition, detailed metabolic assessment of these MEFs confirmed their dependence on glycolysis, and an elevated rate of lactate efflux, associated with the upregulation of glycolytic enzymes known to be associated with tumorigenesis. Correspondingly, Fh1-deficient benign murine renal cysts and an advanced human HLRCC-related renal cell carcinoma manifested a prominent and progressive increase in the expression of HIF-α target genes and in genes known to be relevant to tumorigenesis and metastasis. In accord with our hypothesis, in a variety of different FH-deficient tissues, including a novel murine model of Fh1-deficient smooth muscle, we show a striking and progressive upregulation of a tumorigenic metabolic profile, as manifested by increased PKM2 and LDHA protein. Based on the models assessed herein, we infer that that FH deficiency compels cells to adopt an early, reversible, and progressive protumorigenic metabolic milieu that is reminiscent of that driving the Warburg effect. Targets identified in these novel and diverse FH-deficient models represent excellent potential candidates for further mechanistic investigation and therapeutic metabolic manipulation in tumors.

Systems for the management of respiratory disease in primary care--an international series: Pakistan.

INTRODUCTION: Pakistan has a population exceeding 160 million. Communicable diseases remain the most important health problem in Pakistan, with non-communicable diseases and injuries comprising a quarter of all deaths. NATIONAL POLICY AND HEALTH SERVICE MODEL: The government provides a multi-tiered healthcare system, from the Basic Health Unit at the village level, ranging up to the tertiary care teaching hospitals in the larger cities. These facilities are accessible to all, and are usually free or highly subsidised. Patients have the choice to see a private or government GP, a specialist, or an alternative medicine healer. The current National Health Policy focusses mainly on prevention of communicable diseases, as well as improving primary and secondary health care services. EPIDEMIOLOGY: Only 6% of 13 to 14 year olds are medically diagnosed as having asthma, and more than half report symptoms of rhinitis. The prevalence of chronic bronchitis in patients over 65 is 14% and 6% in rural females and males, respectively, and 9% (with no sex difference) in urban areas. The higher rates of chronic bronchitis observed in females in rural areas may be attributed to high levels of indoor air pollution due to cooking over smoking fires. It is estimated that 36% of adult males, and 9% of females, smoke, and the cigarette consumption per person per year in Pakistan is among the highest in South Asia. Pakistan is ranked 7th among the 22 highest tuberculosis disease burden countries in the world. In 2006 the number of all TB cases was 76,668 compared to 97,245 in 2004. It is estimated that 70-80,000 people are infected with HIV, but only 3,000 AIDS cases have been reported so far. The incidence of acute respiratory infections in children varies, and is a common cause of morbidity. In adults, it is estimated that pneumonia may affect as many as 2.8 million Pakistanis. ACCESS TO CARE: Patients usually can access their local GPs or alternative medical practitioners with relative ease. In villages in remote areas, access to government-run health care facilities can sometimes be quite difficult. FACILITIES AVAILABLE: Respiratory illnesses like asthma, allergy and COPD, are still a relatively low priority area, and even simple equipment--e.g. a peak flow meter--is not commonly available. Specialised equipment like spirometers and allergy testing facilities are only available in a few larger cities and hospitals. FUTURE DEVELOPMENTS: The WHO's Global Alliance against Chronic Respiratory Diseases (GARD) is expected to be launched in 2008. This will be a platform for strengthening primary care respiratory activities with the involvement of the International Primary Care Respiratory Group (IPCRG). Various non-governmental organisations have plans to promote awareness regarding all aspects of allergy, asthma, COPD, and other chronic respiratory diseases, in the future.

The effect of simulated solar UV irradiation on tretinoin in tretinoin gel microsphere 0.1% and tretinoin gel 0.025%.

Topical tretinoin is highly effective and widely used in the treatment of acne vulgaris. Tretinoin gel microsphere 0.1% (TGM)--alone or in combination with erythromycin-benzoyl peroxide (EBP) or clindamycin-benzoyl peroxide (CBP) topical gels-and tretinoin gel 0.025% (TG)--alone or, combined with EBP-were exposed to simulated solar UV irradiation to determine the degree of tretinoin photodegradation/isomerization. The investigation revealed that 94% and 84% of the initial tretinoin in the TGM formulation remained stable after 2 and 6 hours, respectively, of simulated solar UV irradiation. When combined with EBP topical gel, 89% and 81% of the initial tretinoin remained stable after 2 and 6 hours, respectively, of exposure to simulated solar UV irradiation; 86% and 80% of the tretinoin remained stable after 2 and 6 hours, respectively, when combined with CBP topical gel. In contrast, only 19% and 10% of the tretinoin remained unchanged after 2 and 6 hours, respectively, of simulated solar UV irradiation of TG. Combined with the EBP topical gel, undegraded tretinoin quantities were further reduced to 7% and 0% at 2 and 6 hours, respectively, with TG. These data suggest that the TGM formulation offers marked protection against tretinoin photodegradation compared with TG, even in the presence of a topical gel containing a potent antibiotic or a strong oxidizing agent. Although simulated solar UV irradiation is not entirely reflective of actual conditions, the results appear to be substantial.