Biodegradable Hybrid Nanogels for Combination Chemotherapy

Combination chemotherapy is commonly used to treat cancer, because such a therapy regimens usually involve sequential administration of multiple drugs and allow targeting different cell signaling pathway. The co-delivery of drug combination at a controlled ratio via the same vehicle is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and suppression of drug resistance. Undoubtedly, there are several molecular and pharmacological factors that determine the effectiveness of drug combinations. A rationally designed drug combination is required since certain drug ratios and the definitive exposure to the targets of interest can only be synergistic while others are additive or even antagonistic. Cisplatin (CDDP) and paclitaxel (PTX) combination has resulted in improvement in the ovarian cancer treatment compare to individual drug with limited side effects. Multiple clinical trials studied the overall efficacy of CDDP and PTX and found significant benefit over the pre-existing treatments. Since then, this combination has been the treatment of choice for both early stage as well as advanced cases of ovarian cancer. However, administration of two different agents comes with the inconvenience of repeated or extended duration of drug infusion in patients. Moreover, the most extensively used conventional formulation of paclitaxel, Taxol®, utilizes Cremophor EL (polyethoxylated castor oil) that has been linked to significant toxicities including allergic, hypersensitivity and anaphylactic reactions during infusion that require premedication and prolonged peripheral neuropathy. Combining such drugs in one delivery carrier is therefore a well-suited and convenient strategy for controlling the pharmacokinetics and co-delivery of the desired drug ratio in vivo, to maximize the therapeutic potency and minimize drug-associated toxicities. In an attempt to develop such multidrug vehicle, we designed a functional biodegradable and biocompatible polypeptide-based polymeric nanogels. Triblock copolymers containing the blocks of ethylene glycol, glutamic acid and phenylalanine (PEG–PGlu–PPhe) were successfully synthesized via NCA-based ring-opening copolymerization and their composition was confirmed by 1H NMR. Self-assembly behavior of PEG–PGlu90–PPhe25 was utilized for the synthesis of hybrid micelles with PPhe hydrophobic core, cross-linked ionic PGlu intermediate shell layer, and PEG corona. Cross-linked micelles (nanogels, NG) were about 90 nm in diameter (ξ-potential = − 20 mV), uniform (narrow size distribution), and exhibited nanogels-like behavior. Degradation of NG was observed in the presence of proteolytic enzymes (cathepsin B). The resulting NG can incorporate the combination of drugs with very different physical properties such as CDDP (15 w/w% loading) and PTX (9 w/w% loading). Binary drug combination in NG exhibited synergistic cytotoxicity against human ovarian A2780 cancer cells and exerted a superior antitumor activity by comparison to individual drug-loaded NGs or free cisplatin in cancer xenograft model in vivo. However, this system relies solely on the enhanced permeation and retention (EPR) effect to facilitate the delivery of the drug combination to the tumor site. Regardless of the importance and popularity of EPR effect-based drug delivery, this strategy has some limitations related to the inter- and intra-tumor heterogeneity, variations in the density as well as permeability of the tumor vasculature that can affect the accumulation of nanocarriers. One of the popular approaches to circumvent these problems is by surface-functionalization of the drug carrier with ligands that can target receptors with differential expression on the cancer cell surface, which helps in increasing the mean residence time of the delivery system at the tumor site and improving target cell uptake. One such receptor of interest is the folate receptor (FR). Its natural ligand, FA, comes with the advantages of high binding affinity, stability and a simple chemical structure together with ease of availability, making it a suitable targeting ligand for ovarian cancer therapy. FA can thus be successfully conjugated to macromolecular systems without loss of binding affinity to its receptor. Our group has previously demonstrated a tumor-specific delivery and improved anti-cancer effect in vivo of CDDP-loaded NGs decorated with FA targeting groups. In the next part of our study, we designed FA-linked NGs incorporating platinum-taxane combination, and examined whether FR-targeted concurrent delivery of synergistic combination of CDDP and PTX can lead to enhanced therapeutic efficacy compared to nontargeted NG system. FA-decorated NGs significantly suppressed the growth of intraperitoneal ovarian tumor xenografts outperforming their nontargeted counterparts without extending their cytotoxicity to the normal tissues. We also confirmed that synchronized co-delivery of the platinum-taxane drug combination via single carrier to the same targeted cells is more advantageous than a combination of targeted single drug formulations administered at the same drug ratio. Lastly, we demonstrated that the same platform can also be used for localized chemotherapy. Our data indicate that intraperitoneal administration can be more effective in the context of targeted combination therapy. Our findings suggest that multifunctional NGs are promising drug delivery carriers for improvement of current treatment for ovarian cancer. Combination chemotherapy is also very common in the treatment of breast cancer. Trastuzumab (Herceptin™), in combination with chemotherapy is currently used for treatment of ErbB2-overexpressing breast cancers, following surgical removal of the primary tumor. However, patients either do not respond to Trastuzumab based therapies or relapse during the course of the treatment, necessitating the development of newer therapeutics. ErbB2 depends on heat shock protein 90 (HSP90) association for stability and, among client proteins of the chaperone, ErbB2 is perhaps the most sensitive to HSP90 inhibition. HSP90 inhibitors (such as the ansamycin antibiotic, Geldanamycin and related molecules like 17-AAG) have shown significant promise in pre-clinical models of ErbB2-driven breast cancer as well as initial phase I/II clinical trials. The mechanism involves attenuation of oncogenic signaling via degradation of ErbB2 as well as other critical downstream signaling mediators in the pathway, which include phospho-Akt and c-Raf. In a cancer cell, these signaling molecules are strongly dependent on HSP90 to maintain their stability. In a recently completed phase II study of 17-AAG and trastuzumab, an overall clinical benefit (including stable disease) was seen in 57% of the patients with ErbB2-positive metastatic breast cancer progressing on trastuzumab. We therefore hypothesized that HSP90-inhibition will enhance ErbB2-targeted drug delivery by promoting the endocytic uptake of ErbB2-bound nano-encapsulated cargo and facilitating its re-routing from a recycling pathway to the lysosomes. Using Trastuzumab-conjugated NGs (Trast-NG) encapsulating the DNA-damaging drug Doxorubicin (DOX) as a model chemotherapeutic, we demonstrate through both in vitro and in vivo studies that HSP90-inhibition can indeed lead to an enhancement of targeted delivery of DOX specifically into ErbB2-overexpressing breast cancer cells. As a consequence, a sub-therapeutic and non-toxic dose of the HSP90 inhibitor 17AAG markedly improves the efficacy of ErbB2-targetd nanogels in vivo. In a follow up study, we attempted to co-encapsulate DOX and 17-AAG since combining drugs in one delivery carrier is a well-suited strategy for controlling the pharmacokinetics and co-delivery of the desired drug ratio in vivo. However, co-incorporation of drug molecules with different physicochemical properties, such as hydrophilic DOX and hydrophobic 17-AAG, has been challenging. We have recently described biodegradable polymeric nanogels (NGs) based on poly(ethylene glycol)-b-poly(L-glutamic acid) (PEG-b-PGA) with pendant phenylalnine functionalities [23]. Such NGs have multiple hydrophobic domains formed by phenylalanine moieties within the cross-linked PGA polyion cores surrounded by a hydrophilic PEG shell. Herein, we explored these novel NGs for co-encapsulation of 17-AAG and DOX. The potency of this co-delivery system was evaluated in a panel of human breast cancer lines and in an ErbB2-driven orthotopic xenograft model. We demonstrate that NGs-based co-delivery of synergistic combination of 17-AAG and DOX exhibited superior antitumor efficacy compared to a combination of free drugs. The implications of our results may support a new platform for delivery of combinations of HSP90 inhibitors with cytotoxic agents for treatment of various types of cancers

STANDARD MANUFACTURING PROCEDURE PROTOCOL FOR TUTTHA BHASMA AN AYURVEDIC ALCHEMY AND ITS UTILITY

Objective: Standard operating protocol for manufacturing of Tuttha bhasma is a precious metal used in Ayurveda Alchemy Rasa Shastra. Methods: The study was facilitated by collecting Tuttha and was procured from Pharmacy IPGT and RA, Gujarat Ayurved University, Jamnagar. With Grahya Lakshanas (qualities as described in the classics), namely, Snigdha (unctuous), Guru (heavy), and Mahaujjala (very bright blue in color) were observed and selected the sample for the study.Results: From the study, we obtained Tuttha after shodhana is 105 g, 102 g, and 105 g, the average 104% while Marana with Gandhaka media it is 39.2% and in Marana without Gandhaka it is 24.8%.Conclusion: The study confirms that the manufacturings of Tuttha have contained the purification of Gandhak and its utility and the trituratation with Bijora nimbu and heating pattern of Tuttha bhasama

The Fast Fourier Transform Algorithm and Its Application in Digital Image Processing

Transforms are new image processing tools that are being applied to a wide variety of image processing problems. Fourier Transform and similar frequency transform techniques are widely used in image understanding and image enhancement techniques. Fast Fourier Transform (FFT) is the variation of Fourier transform in which the computing complexity is largely reduced. FFT is a mathematical technique for transforming a time domain digital signal into a frequency domain representation of the relative amplitude of different regions in the signal. The objective of this paper is to develop FFT based image processing algorithm. FFT can be computed faster than the Discrete Fourier Transform (DFT) on the same machine. Key words: Fast Fourier Transform, Discrete Fourier Transform, Radix-2 FFT algorithm, Decimation in Time FFT, Time complexity

Deciphering the epidemic synergy of herpes simplex virus type 2 (HSV-2) on human immunodeficiency virus type 1 (HIV-1) infection among women in sub-Saharan Africa

Background: Herpes Simplex Virus Type 2 (HSV-2) is highly prevalent in regions disproportionately affected by the human immunodeficiency virus (HIV-1) epidemic. The objective of our study was to identify the risk factors of HSV-2 and HIV-1 infections and to examine the association between the two infections. Methods: The study participants were recruited through a community based cross-sectional study that was conducted from November 2002 to March 2003 in the Moshi urban district of Northern Tanzania. A two-stage sampling design was used in recruiting the study participants. Information on socio-demographics, alcohol use, sexual behaviors, and STIs symptoms were obtained. Blood and urine samples were drawn for testing of HIV-1, HSV-2 and other STIs. Results: The prevalence of HSV-2 infection among all study participants was 43%. The prevalence rate of HSV-2 among the HIV-negative and HIV-positive women was 40% and 65%, respectively. We found 2.72 times odds of having HIV-1 in an HSV-2 positive woman than in an HSV-2 negative woman. Furthermore, HIV-1 and HSV-2 shared common high-risk sexual behavior factors such as early onset of sexual debut, and testing positive for other STIs. Conclusions: Our findings suggest that HSV-2 may be both a biological and risk-associated cofactor for HIV-1 acquisition. In resource-limited countries, where both infections are prevalent efforts at symptomatic and diagnostic screening and treatment of HSV-2 should be part of HIV-1 prevention programs

FOURIER-TRANSFORM INFRARED SPECTROSCOPY FOURIER INVESTIGATION OF 20 AND 30 PUTI NAGA BHASMA AN AYURVEDIC ALCHEMY AND ITS UTILITY

AIM: To analyze the 20 and 30 puti of Naga bhasma by FTIR technique. MATERIAL AND METHOD: 20 and 30 puti bhasma prepared in the laboratory of the Ithe PGT and RA.and FTIR Analytical parameter is done in IIT Bombay. RESULTS AND OBSERVATIONS: Due to changes in herbal media slight change in frequency in 20 puti and 30 puti. Conclusion: FTIR is a sophisticated technique for the analysis of the Naga bhasma. Discussion: The 20 Puti and 30 puti have different results due to herbal plants used in the processing

Primary Eosinophilic Obliterative Appendicitis

Primary eosinophilic appendicitis is a rare condition of unknown etiology having vague and unexplained symptoms. Histopathological hallmark of this entity is eosinophilic infiltration of the muscularis propria with accompanying edema separating the muscle fibers, and absence of neutrophilic infiltration. Preoperative correct diagnosis of this entity is not possible in view of lack of specific imaging technology. Histopathological examination is the gold standard for the diagnosis. Here, we present an unusual case of Eosinophilic Obliterative appendicitis in a 25 years old male patient

Parent involvement towards children’s reading habit: A focus group survey from Nashik, India

Abstract Purpose - This study was carried out to ascertain parents’ attitude about reading related activities of children, to discover parents’ efforts for instilling the reading habit in their children, to understand the challenges faced by parents in inculcating reading habit in their children, and to suggest possible solutions to the parents’ difficulties related to their children’s reading habits. Design/ Methodology - The research was conducted using the Survey method, with Focus Group Discussion used as the data collection tool. The research sample was 24 parents of pupils who were studying in the primary and secondary Marathi medium schools in Nashik district. An anonymous data was collected Qualitative descriptive analysis was carried out of the collected data. Findings - It was observed that parents knew that pleasure reading was important for the overall behavioral development of their children. However, less than half of them performed any substantial activities to instill the reading habit in their children. Children’s excessive usage of the internet, time constraints, children’s disinterest in reading, and parents’ incognizance about the effective reading material were the main challenges faced. Originality/ Value - This study is one of the first one of its kind in the Indian scenario. Uniquely collecting parents’ real experiences through focus group interviews, this paper provides concrete solutions to the difficulties of parents in inculcating reading habits among their children. Paper type - Research pape

MARINE BIODIVERSITY IN INDIA: LEGAL FRAMEWORK AND CHALLENGES

Marine biodiversity in India encompasses a diverse array of ecosystems, species, and genetic resources, playing a crucial role in the nation's natural heritage and ecological balance. The legal framework governing marine biodiversity primarily consists of legislations such as the Wildlife Protection Act of 1972, Forest (Conservation) Act of 1980, Environment (Protection) Act of 1986, Biological Diversity Act of 2002, and Coastal Regulation Zone (CRZ) notifications. These laws aim to regulate activities affecting marine biodiversity and promote sustainable practices. However, despite the existence of these legal instruments, India faces significant challenges in marine biodiversity conservation, including overfishing, habitat destruction, pollution, and climate change impacts. Insufficient enforcement, inadequate monitoring, and coordination gaps further hinder effective conservation efforts. This paper discusses the legal framework, key challenges, and emphasizes the need for integrated approaches and collaborative efforts to ensure the sustainable management and preservation of India's marine biodiversity. Keywords: Marine biodiversity, National & International legal framework, conservation, challenges & Measures

Cap-hardening parameters of Cam-clay model variations with soil moisture content and shape-restricted regression model

Modeling of soil elastic and permanent plastic volumetric strains (compaction) caused by loading from machinery vehicles using the modified Cam-clay soil constitutive model requires understanding the behaviors of compression and rebound parameters under unsaturated soil conditions.  Oedometer tests were conducted on a sandy loam, a loam, and a clay loam soil, all tropical soils, at three initial soil moisture contents and five maximum stress levels (50, 100, 200, 300 and 400 kPa).  The objectives were to investigate the effects of soil moisture content and maximum applied stress on the modified compression index (l*) and modified rebound index (k*) parameters of a modified Cam-clay soil model on the three soils and predict the compressibility indices using the shape-restricted modeling technique.  The clay loam soil showed higher compressibility at lower maximum stress levels and wet moisture conditions (-10 kPa soil moisture potential) but as the maximum applied stress increased (> 200 kPa), the modified compression index (l*) variations with soil moisture content were insignificant (p > 0.05).  A loam soil exhibited similar compression characteristics to a clay loam soil at 26.12% d.b. and 23.67% d.b., respectively.  For a sandy loam soil, both critical state parameters were less sensitive to the variations in soil moisture content.  The loam soil, which had an organic matter content of 6.33%, rebounded more than clay loam and sandy loam soils especially at higher applied stress values.  On average, the modified compression index (l*) was about 23 to 36 times the modified rebound index (k*).  Shape-restricted and quadratic model fittings are presented to explain the relationship between the critical state parameters and maximum applied stresses for each soil moisture content.  The model fitting results indicated that shape-restricted regression predicted the modified Cam-clay model parameters as a function of maximum applied stress (or pre-compression stress) at very low Average Squared Error Loss (ASEL) and did so better than parametric quadratic equations.   Keywords: modified compression index (l*), modified rebound index (k*), axial stress, uniaxial compression cyclic test, soil moisture, soil type

Assessment of laboratory logistics management information system practice for HIV/AIDS and tuberculosis laboratory commodities in selected public health facilities in Addis Ababa, Ethiopia

Introduction: Logistics management information system for health commodities remained poorly implemented in most of developing countries. To assess the status of laboratory logistics management information system for HIV/AIDS and tuberculosis laboratory commodities in public health facilities in Addis Ababa. Methods: A cross-sectional descriptive study was conducted from September 2010-January 2011 at selected public health facilities. A stratified random sampling method was used to include a total of 43 facilities which, were investigated through quantitative methods using structured questionnaires interviews. Focus group discussion with the designated supply chain managers and key informant interviews were conducted for the qualitative method. Results: There exists a well-designed logistics system for laboratory commodities with trained pharmacy personnel, distributed standard LMIS formats and established inventory control procedures. However, majority of laboratory professionals were not trained in LMIS. Majority of the facilities (60.5%) were stocked out for at least one ART monitoring and TB laboratory reagents and the highest stock out rate was for chemistry reagents. Expired ART monitoring laboratory commodities were found in 25 (73.5%) of facilities. Fifty percent (50%) of the assessed hospitals and 54% of health centers were currently using stock/bin cards for all HIV/AIDS and TB laboratory commodities in main pharmacy store, among these only 25% and 20.8% of them were updated with accurate information matching with the physical count done at the time of visit for hospitals and health centers respectively. Conclusion: Even though there exists a well designed laboratory LMIS, keeping quality stock/bin cards and LMIS reports were very low. Key ART monitoring laboratory commodities were stock out at many facilities at the day of visit and during the past six months. Based on findings, training of laboratory personnel's managing laboratory commodities and keeping accurate inventory control procedures were recommended.Key words: Logistics management information system, stock outs, laboratory commoditie