NOTCH Signaling Pathway: Occurrence, Mechanism, and NOTCH-Directed Therapy for the Management of Cancer.

It is now well understood that many signaling pathways are vital in carrying out and controlling essential pro-survival and pro-growth cellular functions. The NOTCH signaling pathway, a highly conserved evolutionary signaling pathway, has been thoroughly studied since the discovery of NOTCH phenotypes about 100 years ago in Drosophila melanogaster. Abnormal NOTCH signaling has been linked to the pathophysiology of several diseases, notably cancer. In tumorigenesis, NOTCH plays the role of a "double-edged sword," that is, it may act as an oncogene or as a tumor suppressor gene depending on the nature of the context. However, its involvement in several cancers and inhibition of the same provides targeted therapy for the management of cancer. The use of gamma (γ)-secretase inhibitors and monoclonal antibodies for cancer treatment involved NOTCH receptors inhibition, leading to the possibility of a targeted approach for cancer treatment. Likewise, several natural compounds, including curcumin, resveratrol, diallyl sulfide, and genistein, also play a dynamic role in the management of cancer by inhibition of NOTCH receptors. This review outlines the functions and structure of NOTCH receptors and their associated ligands with the mechanism of the signaling pathway. In addition, it also emphasizes the role of NOTCH-targeted nanomedicine in various cancer treatment strategies.

Emerging targeted therapeutic strategies for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC), a subtype of breast cancer that lacks expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), has clinical features including a high degree of invasiveness, an elevated risk of metastasis, tendency to relapse, and poor prognosis. It constitutes around 10-15% of all breast cancer, and having heredity of BRCA1 mutated breast cancer could be a reason for the occurrence of TNBC in women. Overexpression of cellular and molecular targets, i.e. CD44 receptor, EGFR receptor, Folate receptor, Transferrin receptor, VEGF receptor, and Androgen receptor, have emerged as promising targets for treating TNBC. Signalling pathways such as Notch signalling and PI3K/AKT/mTOR also play a significant role in carrying out and managing crucial pro-survival and pro-growth cellular processes that can be utilised for targeted therapy against triple-negative breast cancer. This review sheds light on various targeting strategies, including cellular and molecular targets, signalling pathways, poly (ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and immune checkpoint inhibitors PARP, immunotherapy, ADCs have all found a place in the current TNBC therapeutic paradigm. The role of photothermal therapy (PTT) and photodynamic therapy (PDT) has also been explored briefly.

Advancement in Solubilization Approaches: A Step towards Bioavailability Enhancement of Poorly Soluble Drugs.

A drug's aqueous solubility is defined as the ability to dissolve in a particular solvent, and it is currently a major hurdle in bringing new drug molecules to the market. According to some estimates, up to 40% of commercialized products and 70-90% of drug candidates in the development stage are poorly soluble, which results in low bioavailability, diminished therapeutic effects, and dosage escalation. Because of this, solubility must be taken into consideration when developing and fabricating pharmaceutical products. To date, a number of approaches have been investigated to address the problem of poor solubility. This review article attempts to summarize several conventional methods utilized to increase the solubility of poorly soluble drugs. These methods include the principles of physical and chemical approaches such as particle size reduction, solid dispersion, supercritical fluid technology, cryogenic technology, inclusion complex formation techniques, and floating granules. It includes structural modification (i.e., prodrug, salt formation, co-crystallization, use of co-solvents, hydrotrophy, polymorphs, amorphous solid dispersions, and pH variation). Various nanotechnological approaches such as liposomes, nanoparticles, dendrimers, micelles, metal organic frameworks, nanogels, nanoemulsions, nanosuspension, carbon nanotubes, and so forth have also been widely investigated for solubility enhancement. All these approaches have brought forward the enhancement of the bioavailability of orally administered drugs by improving the solubility of poorly water-soluble drugs. However, the solubility issues have not been completely resolved, owing to several challenges associated with current approaches, such as reproducibility in large scale production. Considering that there is no universal approach for solving solubility issues, more research is needed to simplify the existing technologies, which could increase the number of commercially available products employing these techniques.

Doxorubicin Conjugates: An Efficient Approach for Enhanced Therapeutic Efficacy with Reduced Side Effects.

Continuous drug delivery modification is the scientific approach and is a basic need for the efficient therapeutic efficacy of active drug molecules. Polymer-drug conjugates have long been a hallmark of the drug delivery sector, with various conjugates on the market or in clinical trials. Improved drug solubilization, extended blood circulation, decreased immunogenicity, controlled release behavior, and increased safety are the advantages of conjugating drugs to the polymeric carrier like polyethylene glycol (PEG). Polymer therapies have evolved over the last decade, resulting in polymer-drug conjugates with diverse topologies and chemical properties. Traditional nondegradable polymeric carriers like PEG and hydroxy propyl methacrylate have been clinically employed to fabricate polymer-drug conjugates. Still, functionalized polymer-drug conjugates are increasingly being used to increase localized drug delivery and ease of removal. Researchers have developed multifunctional carriers that can "see and treat" patients using medicinal and diagnostic chemicals. This review focused on the various conjugation approaches for attaching the doxorubicin to different polymers to achieve enhanced therapeutic efficacy, that is, increased bioavailability and reduced adverse effects.

Validation of a Novel Supercritical Fluid Extractor/Dryer Combo Instrument.

The current pharmaceutical manufacturing scenario involves different techniques for the processing of materials. For example, the extraction unit is one of the essential aspects of plant-based pharmaceuticals. Recently, various kinds of extraction techniques have been used for analytical and preparative scales; among them, a supercritical fluid extractor (SCFE) is the most widely used technique for extraction. It is used for an extensive range of crude drugs and can be possible with the help of SCFE by varying temperature/pressure. Notably, it uses carbon dioxide (CO2) for extraction instead of other solvents. Simultaneously, lyophilization is an important technique used at different processing steps along with other methods. In lyophilization, CO2 is used as a cooling agent in the shelves of lyophilized equipment. It behaves as a supercritical fluid at critical pressure (Pc) of 72.7 atm and critical temperature (Tc) of 31°C. Considering the criteria mentioned earlier, there is a possibility that liquid CO2 or supercritical carbon dioxide (SC-CO2) can be used as a cooling agent in a lyophilizer and extraction solvent in SCFE. This review presents a brief outline for the possible validation parameters of the proposed novel processor; that is, SCFE/Dryer combo instrument containing Design Qualification, Installation Qualification, Operational Qualification, and Performance Qualification.

Excitonic enhancement of colour emission and Förster resonance energy transfer in chemically synthesized Mn-doped ZnS nanomaterials.

This study has been carried out to understand the mechanism of charge carrier dynamics and the existence of exciton-dopant energy transfer within Mn-doped ZnS nanomaterials. Improvement in the energy transfer efficiency and electroluminescence properties of these nanomaterials has been investigated for using them as an emissive layer of LEDs. A chemical co-precipitation method has been used to synthesize ZnS with varying Mn contents to achieve enhanced luminescence properties demonstrating the effect of Mn doping on excitonic luminescence intensity. X-ray powder diffraction analysis reveals the prepared materials to be cubic crystallites with size varying between 2 nm and 4 nm. Agglomerated clusters and a nanogranular morphology have been observed in SEM analysis. The UV-Vis spectra reveal that the band gaps slightly decrease with an increase in the Mn content in ZnS samples. The photoluminescence spectra show that upon Mn incorporation, the intensity of blue emission at 420 nm increases due to the surface states in ZnS; an orange emission at 588 nm is also observed due to a transition within Mn2+. The energy transfer efficiency of 3 to 6% was measured theoretically by using the FRET (Förster resonance energy transfer) model. Mn-doped ZnS shows high photoluminescence quantum yield (QY) in comparison with ZnS, where 0.04 mol% Mn-doped ZnS achieved the highest QY of about 28.94%. The CIE chromaticity coordinates accordingly shift toward white from the blue region upon Mn substitution. A kinetic model has been used to determine the energy transfer efficiency, which affects the luminescence properties of ZnS. The FRET model has suitably unraveled the Förster radius and interatomic distance, which make the energy transfer possible in these materials. We have found 0.04 mol% Mn-doped ZnS with an enhanced energy transfer efficiency. The maximum external quantum efficiency of about 0.643% can be achieved at 2.9 volts of operating voltage for this nanomaterial. These highly luminescent materials possess the characteristics of an emissive layer to be used for light-emitting applications.

Histopathology of the right ventricular outflow tract and the relation to hemodynamics in patients with repaired tetralogy of Fallot.

OBJECTIVE: To evaluate the relationship between myocardial histopathology and tissue Doppler imaging (TDI) variables of the right ventricle and postoperative peak systolic right-to-left ventricular pressure ratio (Prv/Plv) in patients undergoing intracardiac repair for tetralogy of Fallot (TOF). METHODS: Operatively resected crista supraventricularis muscle specimens from 93 patients undergoing intracardiac repair for TOF, aged 18 months to 26 years (mean, 7.02 ± 5.35 years) were subjected to light microscopy. TDI-derived parameters between the normal and abnormal categories of myocardium, the evolution of Prv/Plv, and its relationship to TDI-derived variables were tested using generalized linear random effects model using xtreg command. RESULTS: The incidence of myocyte hypertrophy, myocytolysis, and perivascular fibrosis was 89.2%, 83.8%, and 77.4%, respectively. Although tricuspid annular peak systolic excursion, peak myocardial velocity during systole (s'), and early diastolic basal lengthening of right ventricle (e') continued to improve among patients with myocardial hypertrophy, myocytolysis, and perivascular fibrosis, there was an absence of improvement of the late diastolic relaxation of right ventricular free wall (a') in patients with perivascular fibrosis. Although there was improvement of postoperative Prv/Plv in patients with myocardial fibrosis as compared with normal histology, the values were not statistically significant (ß [standard error] -0.07 [0.08], P = .3). CONCLUSIONS: The great majority of myocardial tissues in cyanotic TOF indicate pre-existing hypertrophic, degenerative, and fibrotic changes. Perivascular fibrosis affects the diastolic compliance of the right ventricle and may account for the absence of improvement of late diastolic relaxation (a') and greater postoperative Prv/Plv in the absence of a residual surgical lesion.

Trastuzumab decorated TPGS-g-chitosan nanoparticles for targeted breast cancer therapy.

Breast cancer, up-regulated with human epidermal growth factor receptor type-2 (HER-2) has led to the concept of developing HER-2 targeted anticancer therapeutics. Docetaxel-loaded D-α-tocopherol polyethylene glycol 1000 succinate conjugated chitosan (TPGS-g-chitosan) nanoparticles were prepared with or without Trastuzumab decoration. The particle size and entrapment efficiency of conventional, non-targeted as well as targeted nanoparticles were in the range of 126-186 nm and 74-78% respectively. In-vitro studies on SK-BR-3 cells showed that docetaxel-loaded non-targeted and HER-2 receptor targeted TPGS-g-chitosan nanoparticles have enhanced the cellular uptake and cytotoxicity with a promising bioadhesion property, in comparison to conventional formulation i.e., Docel™. The IC50 values of non-targeted and targeted nanoparticles from cytotoxic assay were found to be 43 and 223 folds higher than Docel™. The in-vivo pharmacokinetic study showed 2.33, and 2.82-fold enhancement in relative bioavailability of docetaxel for non-targeted and HER-2 receptor targeted nanoparticles, respectively than Docel™. Further, after i.v administration, non-targeted and targeted nanoparticles achieved 3.48 and 5.94 times prolonged half-life in comparison to Docel™. The area under the curve (AUC), relative bioavailability (FR) and mean residence time (MRT) were found to be higher for non-targeted and targeted nanoparticles when compared to Docel™. The histopathology studies of non-targeted and targeted nanoparticles showed less toxicity on vital organs such as lungs, liver, and kidney when compared to Docel™.

A Comparative Study of Histopathological Changes in the Ascending Aorta and the Risk Factors Related to Histopathological Conditions and Aortic Dilatation in Patients With Tetralogy of Fallot and a Functionally Univentricular Heart.

BACKGROUND: The purposes of this study were to prospectively evaluate the histologic characteristics of the aortic wall of patients undergoing univentricular type of repair and compare the same with the findings observed in patients undergoing intracardiac repair of tetralogy of Fallot (TOF). PATIENTS AND METHODS: Operatively excised full-thickness aortic wall tissue from 99 consecutive patients undergoing either intracardiac repair of TOF (group I; n=42) or univentricular repair (group II; n=57) were studied by light microscopy. Age at operation was 13 months to 28 years (mean 99.97±73.21months) for group I and 9 months to 25 years (mean 79.52±60.09) months for group II patients. RESULTS: Dilatation of the ascending aorta was present in 85.7% patients with TOF and 91.2% patients with a univentricular heart. Seventeen (17.2%) aortic specimens were histologically normal and were used as normal controls (group I, n=5; group II, n=12). A lamellar count of less than 60 was associated with a sensitivity of 97.2% and a specificity of 66.7% in patients undergoing repair of TOF and a sensitivity of 84.6% and a specificity of 80% in patients undergoing univentricular type of repairs respectively. Patients undergoing intracardiac repair of TOF and those undergoing univentricular repair exhibited 23.67 times (15.91-147.40) and 8.48 times (3.62-15.84) increased risk of aortic dilatation respectively. CONCLUSIONS: Our findings indicate the existence of significant elastic fragmentation, muscle disarray, medionecrosis and fibrosis involving the ascending aortic media in patients with a functionally univentricular heart and dilated aorta. These histopathological changes are similar to those encountered in patients with TOF and dilated aorta.

Mitral Valve Replacement Using Carpentier-Edwards Pericardial Bioprosthesis in Patients With Rheumatic Heart Disease Aged Below 40 Years: 17-Year Results.

BACKGROUND: This study was designed to evaluate patients aged less than 40 years implanted with tissue heart valves with respect to survival, thromboembolism, structural degeneration and quality of life. METHODS: Between January, 2000 and December, 2016, 132 patients (51 males) with rheumatic heart disease underwent mitral valve replacement using Carpentier-Edwards, perimount, pericardial bioprostheses. The patients' ages ranged between 12 and 39 years (mean±SD 30.12±5.51 years). RESULTS: The hospital and late mortality were 1.5% and 1.5% respectively. The total cumulative follow-up period was 1330.98 patient-years with a mean of 124.78±50.3 months (range, 1-204 months). The actuarial survival and actuarial event-free survival at 204 months was 96.9% (±0.01%) and 93.4%(±0.03%) respectively. There was one episode of thromboembolism (0.32 events per 100 patient years). Six (4.7%) patients underwent redo mitral valve replacement for severe bioprosthetic degeneration with stiffening and calcification using a Medtronic mechanical prosthesis (Medtronic Open Pivot, MN, USA). CONCLUSIONS: We conclude that Carpentier-Edwards perimount pericardial prosthesis provides satisfactory clinical performance in a young population with a low risk of degeneration and other valve-related events.

RGD-TPGS decorated theranostic liposomes for brain targeted delivery.

The aim of this work was to formulate RGD-TPGS decorated theranostic liposomes, which contain both docetaxel (DTX) and quantum dots (QDs) for brain cancer imaging and therapy. RGD conjugated TPGS (RGD-TPGS) was synthesized and conjugation was confirmed by Fourier transform infrared (FTIR) spectroscopy and electrospray ionisation (ESI) mass spectroscopy (ESI-MS). The theranostic liposomes were prepared by the solvent injection method and characterized for their particle size, polydispersity, zeta-potential, surface morphology, drug encapsulation efficiency, and in-vitro release study. Biocompatibility and safety of theranostic liposomes were studied by reactive oxygen species (ROS) generation study and histopathology of brain. In-vivo study was performed for determination of brain theranostic effects in comparison with marketed formulation (Docel™) and free QDs. The particle sizes of the non-targeted and targeted theranostic liposomes were found in between 100 and 200nm. About 70% of drug encapsulation efficiency was achieved with liposomes. The drug release from RGD-TPGS decorated liposomes was sustained for more than 72h with 80% of drug release. The in-vivo results demonstrated that RGD-TPGS decorated theranostic liposomes were 6.47- and 6.98-fold more effective than Docel™ after 2h and 4h treatments, respectively. Further, RGD-TPGS decorated theranostic liposomes has reduced ROS generation effectively, and did not show any signs of brain damage or edema in brain histopathology. The results of this study have indicated that RGD-TPGS decorated theranostic liposomes are promising carrier for brain theranostics.