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Sugar alcohol-modified polyester nanoparticles for gene delivery via selective caveolae-mediated endocytosis
No full textNucleic acid-based drugs are changing the scope of emerging medicine in preventing and treating diseases. Nanoparticle systems based on lipids and polymers developed to navigate tissue-level and cellular-level barriers are now emerging as vector systems that can be translated to clinical settings. A class of polymers, poly(β-amino esters) (PBAEs) known for their chemical flexibility and biodegradability, has been explored for gene delivery. These polymers are sensitive to changes in the monomer composition affecting transfection efficiency. Hence to add functionality to these polymers, we partially substituted ligands to an identified effective polymer chemistry. We report here a new series of statistical copolymers based on PBAEs where the backbone is modified with sugar alcohols to selectively facilitate the caveolae-mediated endocytosis pathway of cellular transport. These ligands are grafted at the polymer's backbone, thereby establishing a new strategy of modification in PBAEs. We demonstrate that these polymers form nanoparticles with DNA, show effective complexation and cargo release, enter the cell via selective caveolae-mediated endocytosis, exhibit low cytotoxicity, and increase transfection in neuronal cells
Enhancing the antibacterial efficacy of vancomycin analogues: targeting metallo-β-lactamases and cell wall biosynthesis
No full textVancomycin is a crucial last-resort antibiotic for tackling Gram-positive bacterial infections. However, its potency fails against the more difficult-to-treat Gram-negative bacteria (GNB). Vancomycin derivatives have shown promise as broad-spectrum antibacterials, but are still underexplored. Toward this, we present a novel strategy wherein we substitute the sugar moiety of vancomycin with a dipicolyl amine group, yielding VanNHdipi. This novel glycopeptide enhances its efficacy against vancomycin-resistant bacteria by up to 100-fold. A comprehensive approach involving microbiological assays, biochemical analyses, proteomics, and computational studies unraveled the impact of this design on biological activity. Our investigations reveal that VanNHdipi, like vancomycin, disrupts membrane-bound steps of cell wall synthesis inducing envelope stress, while also interfering with the structural integrity of the cytoplasmic membrane, setting it apart from vancomycin. Most noteworthy is its potency against critical GNB producing metallo-β-lactamases (MBLs). VanNHdipi effectively inactivates various MBLs with IC50 in the range of 0.2–10 μM resulting in resensitization of MBL-producing bacteria to carbapenems. Molecular docking and molecular dynamics (MD) studies indicate that H-bonding interactions between the sugar moiety of the vancomycin derivative with the amino acids on the surface of NDM-1 facilitate enhanced binding affinity for the enzyme. This work expands the scope of vancomycin derivatives and offers a promising new avenue for combating antibiotic resistance
Sulfur dioxide (so2) releasing polymeric systems: design, synthesis, and potential biomedical applications.
No full textIn the area of nanomedicines, recently, gasotransmitters have gained much attention as green strategies for various biomedical applications. Sulfur dioxide (SO2), a member of gasotransmitters, has an enormous effect on regulating the structure and function of blood vessels, nervous system, gastrointestinal tract, etc. However, the pharmaceutical use of SO2 gas has been obstructed due to the administration problem owing to its negligible stability under physiological conditions. In addition, the lack of control delivery at the targeted sites and the toxicity at high concentrations further limit its applications. To date, a wide array of SO2-delivering molecules have been designed to address these issues. Despite some success, these small molecular SO2 donors encounter limitations such as short half-lives, shelf lives, and circulation times. Therefore, fabrications of different SO2 delivering systems with on-demand release behavior are of serious need for precise delivery. In these contexts, polymeric SO2 donors have emerged as promising choices due to notable advantages in terms of control release, water solubility, and extremely versatile nature to meet clinical requirements. Herein, we summarize the synthetic strategy and SO2 release mechanism of recently developed polymeric SO2-delivering agents. Additionally, the physiological importance of SO2 and the advancement of the small molecular SO2 donors are also discussed. We envisage that this review article will aid researchers in developing potent SO2-releasing polymeric systems for paving the way toward the next generation of SO2-based gas therapy
Demographic and clinical profile of 1106 adult soft tissue sarcoma patients: A single institutional prospective database experience from India
No full textBackground
Adult soft tissue sarcomas (STS) are rare and diverse. Current management is based on limited literature from the West. Therefore, data from different geographical regions is required, including the low-middle-income countries. This is our experience managing adult sarcomas in the tertiary cancer center of North India.
Materials and methods
This is a retrospective analysis of the structured sarcoma database of patients treated in the surgical oncology department between 1992 and 2020. The descriptive analysis includes demography, site distribution, diagnosis, histopathology variations, prior surgical interventions, and stage.
Results
A total of 1106 soft tissue sarcoma patients were treated in three decades. Age distribution was 13%, 43%, 31%, and 11% in >20, 21–40, and 41–60 and >60 years, respectively. The male-to-female ratio was 1.73. The anatomical distribution was 17%, 42%, 23%, 7%, 7%, and 3% in upper extremity, lower extremity, trunk, retroperitoneum, head and neck, and viscera, respectively. Overall, 49% of patients had undergone prior suboptimal surgeries at community hospitals. Common histology subtypes were synovial sarcoma (18%), undifferentiated pleomorphic sarcoma (UPS) (13%), dermatofibrosarcoma protuberans (12%), and liposarcoma (9%). A pathological discordance of 13% was identified between the initial and the final histologies. Overall, 61% of tumors were high-grade. Memorial Sloan Kettering Stages II and III were present in 33% and 35% of patients, respectively.
Conclusions
This is one of the largest single institutional experiences of STS from the Asian population. Mostly young adults were affected with male preponderance. The lower extremity and trunk were common subsites. Frequent histologies were synovial sarcoma and UPS. A high rate of suboptimal surgical intervention at the community level and pathological discordance was noted. This study highlights the need to establish prospective structured databases for capturing quality information related to rare malignancies and providing insights for future research
Dual stimuli-responsive biotinylated polymer–drug conjugate for dual drug delivery.
No full textStimuli-responsive nanoscale polymer–drug conjugates are one of the most promising alternatives in the realm of advanced therapeutics, rendering several characteristics such as spatio-temporal control over drug release, reduced off-target toxicity, enhanced bioavailability, and longer blood circulation time of the drug. Fostered by the aforementioned conceptualization, our quest to develop an ideal polymer–drug conjugate has originated the present investigation of developing a reactive oxygen species (ROS) and esterase-responsive self-assembled polymer–drug (chlorambucil, CBL) conjugate with biotin pendants (DP2) for cancer cell targeting, surrogating another antineoplastic drug, doxorubicin (DOX) via physical encapsulation (DP2@DOX). The ROS and esterase trigger not only released the covalently stitched CBL but also resulted in DOX release by dismantling the amphiphilic balance of the nanoaggregates. Biotinylation-mediated enhancement of cellular uptake of DP2@DOX was reflected in the synergistic anticancer activity of both the drugs (CBL and DOX) in HeLa cells (biotin receptor-positive cells) compared to HEK 293T cells (biotin receptor-negative cells). Furthermore, the selective internalization of the fluorophore-tagged DOX-loaded polymer (DP4@DOX) in HeLa cells compared to HEK 293T cells was confirmed by confocal microscopy and flow cytometry. In summary, the present investigation demonstrates a state-of-the-art self-assembled polymer–drug conjugate as a next-generation dual stimuli-responsive drug delivery vehicle
Management and Outcomes of Children with Malignant Germ Cell Tumor
No full textObjectives
To assess the clinico-pathological features, management and outcomes, amongst extracranial malignant germ cell tumors (MGCTs) in children treated primarily at a tertiary care center in a resource-challenged nation.
Methods
The prospectively maintained data for children below 14 y of age treated for extracranial MGCT from May 1994 to January 2023 was analyzed for patient characteristics, management, event-free survival (EFS) and overall survival (OS) and factors effecting survival. Events was defined as death, recurrence and progression. Multivariate logistic regression analysis was performed to identify the factors independently predicting unfavorable outcomes.
Results
One hundred and seventy-seven children (37% males) with a median (IQR) age at presentation of 30 mo (range 2–168 mo) were included. The cohort consisted of 87 (49%) extra-gonadal and 90 (51%) gonadal cases. Disease was metastatic at presentation in 48 (27%) with lungs being the most common site. Neoadjuvant chemotherapy (NACT) was given to 119 (67%) and finally 162/177 (92%) had undergone resection of the primary tumor. Endodermal sinus tumor (EST) was the commonest histological subtype in 141 children (73%). Twenty-two (12%) patients had died giving a 5-y OS of 84.7% (95% CI 78.3- 91.1). Recurrence occurred in 25 patients, and an additional 5 patients had progression giving a 5-y EFS of 69.9% (95% CI 62.5- 77.3). Stage III (p = 0.05), Stage IV (p = 0.006) and extra-gonadal site (p = 0.05) were significantly associated with poorer EFS.
Conclusions
Children with MGCT have a favorable outcome with 5-y OS of 84.7% and EFS of 69.9%. Stage III and IV disease and extra-gonadal sites were independent predictors of a poor outcome
STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response
No full textHematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin-ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs
Comparison of HASTE versus EPI-Based DWI for Retinoblastoma and Correlation with Prognostic Histopathologic Parameters
No full textBACKGROUND AND PURPOSE: Non-EPI-based DWI has shown better performance in head and neck pathologies owing to lesser susceptibility artifacts compared with EPI-DWI. However, only sporadic studies have investigated the feasibility of non–EPI-based DWI in retinoblastoma (RB). We qualitatively and quantitively compared EPI-DWI and HASTE-DWI in RB and correlated the tumor ADC values obtained from these 2 techniques with histopathologic markers.
MATERIALS AND METHODS: Twenty-one treatment-naive patients with RB underwent 1.5T orbital MR imaging. EPI-DWI and HASTE-DWI were acquired at 3 b-values (0, 500, and 1000 s/mm2). All patients subsequently underwent surgical enucleation. For qualitative image assessment, scoring of overall image quality, artifacts, tumor sharpness, and tumor conspicuity was done by using a 5-point Likert scale. Quantitative assessment included calculations of SNR, contrast-to-noise ratio (CNR), geometric distortion, and ADC. Qualitative scores were compared by using the Wilcoxon signed-rank test, and quantitative parameters were analyzed with a t test.
RESULTS: All 21 patients had unilateral RB; 15 were male and 6 were female with a median age of 36 months (range, 9–72 months). On histopathology, patients had either poorly differentiated (n = 13/21) or moderately differentiated (n = 8/21) RB. Other poor prognostic markers evaluated were optic nerve invasion (n = 10/21), choroidal invasion (n = 12/21), and anterior eye segment enhancement on MRI (n = 6/21). HASTE-DWI demonstrated higher image quality scores than EPI-DWI (P < .01), except for tumor conspicuity score, which was higher for EPI-DWI (P < .001). HASTE-DWI showed lower SNR, CNR, and geometric distortion than EPI-DWI (P < .001). The average acquisition times of EPI-DWI and HASTE-DWI were ∼1 and 14 minutes, respectively. The mean tumor ADC value on EPI-DWI was 0.62 ± 0.14 × 10−3 mm2/s and on HASTE-DWI was 0.83 ± 0.17 × 10−3 mm2/s. A significant correlation between EPI-DWI and HASTE-DWI ADC values (r = 0.8; P = .01) was found. Lower ADC values were found in tumors with poor prognostic markers, but none reached a statistically significant difference.
CONCLUSIONS: HASTE-DWI shows improved overall image quality; however, it lacks in terms of tumor conspicuity, SNR, CNR, and longer acquisition time compared with EPI-DWI. ADC values derived from HASTE-DWI show no advantage over EPI-DWI in correlation with histopathologic prognostic markers
Insights into Cumulative Impact of Channel Estimation Errors on RIS Phase-Shift Configuration and Data Demodulation
No full textIn a reconfigurable intelligent surface (RIS)-aided downlink, channel estimation errors due to noise during training lead to a sub-optimal RIS phase-shift configuration. This degrades the RIS beamforming gain. Furthermore, the errors lead to an imperfect estimate of the degraded beamforming gain itself. We analyze the cumulative impact of these errors on the achievable rate. We present two innovations that make our analysis tractable and insightful. First, we present a novel approximation for the effective downlink channel gain in the presence of estimation errors. Second, we prove that the central limit theorem applies to the effective downlink channel gain even in the presence of estimation errors and correlated cascaded channels due to closely-spaced RIS elements. Our analysis leads to insightful closed-form expressions for the optimal pilot and data powers that maximize the rate. The optimal power allocation achieves a significantly higher rate than the conventional approach that assigns equal power to pilots and data
One-pot synthesized plasmonic black gold nanoparticles for efficient photocatalytic CO oxidation
No full textDendritic plasmonic colloidosome, also known as “black gold”, is a unique plasmonic material with broad-spectrum light absorption extending from visible to near-infrared wavelengths. Black gold has demonstrated remarkable performance in challenging and industrially relevant reactions, such as CO2 reduction, alcohol oxidation, acetylene semi-hydrogenation, and purification of seawater. Unfortunately, one of the major shortcomings of black gold lies in its intricate multi-step synthesis procedure. This involves the step-by-step growth of Au nanoparticles on a dendritic fibrous nanosilica (DFNS) support, a task spanning several days. Furthermore, the need for solid separation through centrifugation after each cycle is an additional bottleneck. Consequently, this complexity poses a challenge for industrial scaling. In this work, we report a simplified and efficient one-pot synthesis of plasmonic black gold. The one-pot method streamlines the synthesis process, significantly reducing the time from days to hours and eliminating the need for solid separation steps, thereby enhancing sustainability. Characterization studies reveal the optimal reaction time of an hour (instead of days) during the growth step, resulting in black gold materials closely resembling those synthesized via the conventional cycle-by-cycle method. We further demonstrated that DPC-60 synthesized via a one-pot protocol efficiently catalyzes CO oxidation under light, achieving 87% CO conversion at 4.0 W cm−2 without external heating. In situ DRIFTS studies revealed key adsorption sites involved in the CO oxidation reaction, with bridged CO adsorbed on Au0 sites reacting faster than linearly adsorbed CO, and CO on high-coordinated Au0 sites exhibiting a faster reaction rate than that on low-coordinated sites. Thus, the one-pot synthesis will facilitate rapid exploration of black gold's applications in a range of fields and also pave the way for scalable industrial deployment