Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial.

BACKGROUND: Measurement of fractional flow reserve (FFR) has an established role in guiding percutaneous coronary intervention. We tested the hypothesis that, at the stage of diagnostic invasive coronary angiography, systematic FFR-guided assessment of coronary artery disease would be superior, in terms of resource use and quality of life, to assessment by angiography alone. METHODS: We performed an open-label, randomized, controlled trial in 17 UK centers, recruiting 1100 patients undergoing invasive coronary angiography for the investigation of stable angina or non-ST-segment-elevation myocardial infarction. Patients were randomized to either angiography alone (angiography) or angiography with systematic pressure wire assessment of all epicardial vessels >2.25 mm in diameter (angiography+FFR). The coprimary outcomes assessed at 1 year were National Health Service hospital costs and quality of life. Prespecified secondary outcomes included clinical events. RESULTS: In the angiography+FFR arm, the median number of vessels examined was 4 (interquartile range, 3-5). The median hospital costs were similar: angiography, £4136 (interquartile range, £2613-£7015); and angiography+FFR, £4510 (£2721-£7415; P=0.137). There was no difference in median quality of life using the visual analog scale of the EuroQol EQ-5D-5L: angiography, 75 (interquartile range, 60-87); and angiography+FFR, 75 (interquartile range, 60-90; P=0.88). The number of clinical events was as follows: deaths, 5 versus 8; strokes, 3 versus 4; myocardial infarctions, 23 versus 22; and unplanned revascularizations, 26 versus 33, with a composite hierarchical event rate of 8.7% (48 of 552) for angiography versus 9.5% (52 of 548) for angiography+FFR (P=0.64). CONCLUSIONS: A strategy of systematic FFR assessment compared with angiography alone did not result in a significant reduction in cost or improvement in quality of life. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01070771.

Direct evidence of cellular transformation by prion-like p53 amyloid infection.

Tumor suppressor p53 mutations are associated with more than 50% of cancers. Aggregation and amyloid formation of p53 is also implicated in cancer pathogenesis, but direct evidence for aggregated p53 amyloids acting as an oncogene is lacking. Here, we conclusively demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to non-cancerous cells. p53 amyloid aggregates were transferred through cell generations, contributing to enhanced survival, apoptotic resistance with increased proliferation and migration. The tumorigenic potential of p53 amyloid-transformed cells was further confirmed in mouse xenografts, wherein the tumors showed p53 amyloids. p53 disaggregation rescued the cellular transformation and inhibited tumor development in mice. We propose that wild-type p53 amyloid formation contributes to tumorigenesis and can be a potential target for therapeutic intervention. This article has an associated First Person interview with the first author of the paper.

Effect of Kangen and reverse osmosis water on dental plaque, salivary pH and salivary Streptococcus mutans counts: a randomized-controlled trial (A preliminary study).

PURPOSE: The present randomized-controlled trial was conducted to assess the effect of Kangen water and reverse osmosis (RO) water on dental plaque, salivary pH and salivary Streptococcus mutans count. MATERIALS AND METHODS: This randomized control trial was conducted for 14 days on 24 randomly selected participants from the pool of undergraduate dental students. Participants were randomly divided into two groups of 12 each: the Kangen water (pH 9) group and the RO water group. Participants in each group were asked to drink allocated water for 7 days. Dental plaque, salivary pH and microbial colony-forming units (CFUs) were assessed after 7 and 14 days. RESULTS: Intragroup comparison showed that all three outcomes showed a significant improvement in the Kangen water group after 14 days, whereas no difference was seen in the RO water group. Intergroup comparison showed a significant difference in plaque score and CFU among the two groups after 7 and 14 days, whereas pH between the two groups did not show a significant difference. CONCLUSIONS: Regular drinking of alkaline Kangen water with pH 9 was found to be effective in reducing plaque and salivary Streptococcus mutans count when compared to RO water.

In vitro and in vivo anti-inflammatory activity of Tetrastigma sulcatum leaf extract, pure compound and its derivatives.

The severity and perseverance of inflammation have been demonstrated in many health conditions. The limitations of existing medications suggest the need for new alternative anti-inflammatory medications. In our earlier studies, we demonstrated the topical anti-inflammatory potential of the crude ethanolic extract of Tetrastigma sulcatum leaves and its fractions. In the present study, we further explored the anti-inflammatory activity of T. sulcatum extract, fractions, pure compound and its derivatives using in vitro and in vivo bioassay techniques. We attempted to isolate a pure compound from the leaf extract and identified it as a Friedelan-3ß-ol (CI). Furthermore, Friedelinol acetate (C II) and friedelinol methyl ether (C III), derivatives of Friedelan-3ß-ol (CI) were synthesised. LPS-induced inflammatory RAW 264.7 macrophages were used as in vitro model to study anti-inflammatory and anti-oxidative effects. Inflammation-induced oxidative damage was found to be restricted significantly (P < 0.001), with scavenging activity and increased SOD activity of crude extract and fractions. Treatment with crude extract (TSETOH) and fractions (TSHEX, TSTOL) significantly reduced (P < 0.001) the mRNA expression of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α) and nitric oxide (NO) production in LPS-stimulated inflammation in RAW 264.7 cells in a dose-dependent manner. Likewise, compounds CI and CIII showed a similar pattern of significant inhibition (P < 0.001) of pro-inflammatory cytokines and NO production in a dose-dependent manner. An in vivo study in a carrageenan-induced mouse paw oedema model demonstrated reduced paw oedema and pro-inflammatory cytokines in a dose-dependent manner upon treatment with the extract, its fractions, pure compound (CI), and their derivatives (CII, and CIII). The present study confirmed the anti-inflammatory activity of T. sulcatum, suggesting that Friedelan-3ß-ol is an active component of the crude extract.

Antioxidant-antibacterial containing bi-layer scaffolds as potential candidates for management of oxidative stress and infections in wound healing.

Tissue engineering techniques are continuously evolving towards providing better microenvironment along with therapeutic potential to address the skin tissue defects. Factors such as microbial infections, presence of excessive free radicals and depletion in antioxidant based scavenging systems pose serious challenges by prolonging inflammation and delaying the repair process. Incorporation of bioactive molecules in polymer based biomimetic scaffolds may present new vistas for handling chronic wounds. In this study, chitosan/collagen scaffolds incorporating 0.5, 1 and 2% (w/w) silymarin (CS-CO-SM) were synthesized and studied for their biocompatibility, in vitro release kinetics and anti-oxidant activity. The release kinetics of silymarin from the CS-CO-SM scaffold showed an initial burst followed by sustained release. The scaffolds were biocompatible and supported the recovery of COS-7 cells from UV induced oxidative stress. Further the CS-CO-SM(2) scaffolds were used to fabricate a bi-layer scaffold by layer upon layer arrangement with CS-Ag3 (3% Ag, w/w). The Ag was incorporated to impart antimicrobial property to the scaffold. The in vivo studies on bi-layer scaffolds were carried out in Wistar rat models at 3, 7 and 10 days post injury and the skin excisions were studied for wound contraction, histology (H&E staining), and lipid peroxidation. The bi-layer scaffold accelerated the process of wound healing with no inflammatory cells, proliferation of fibroblast, neovascularization and collagen deposition. By day 10 post transplantation of the scaffold, the skin had a structure similar to normal skin with complete re-epithelization. This bi-layer scaffold with antioxidant and antimicrobial properties promotes wound healing and is proposed as a potential tissue engineering material for managing chronic wounds.

Effect of combined radiation injury on cell death and inflammation in skin.

In the event of a nuclear disaster, the individuals proximal to the source of radiation will be exposed to combined radiation injury. As irradiation delays cutaneous repair, the purpose of this study was to elucidate the effect of combined radiation and burn injury (CRBI) on apoptosis and inflammation at the site of skin injury. Male C57Bl/6 mice were exposed to no injury, thermal injury only, radiation only (1 and 6 Gy) and CRBI (1 and 6 Gy) and euthanized at various times after for skin collection. TUNEL staining revealed that the CRBI 6 Gy group had a delayed and increased apoptotic response. This correlated with decreased recovery of live cells as compared to the other injuries. Similar response was observed when cleaved-caspase-3 immunohistochemical staining was compared between CRBI 6 Gy and thermal injury. TNFR1, caspase 8, Bax and IL-6 mRNA expression revealed that the higher CRBI group had delayed increase in mRNA expression as compared to thermal injury alone. RIPK1 mRNA expression and necrotic cell counts were delayed in the CRBI 6 Gy group to day 5. TNF-α and NFκB expression peaked in the CRBI 6 Gy group at day 1 and was much higher than the other injuries. Also, inflammatory cell counts in the CRBI 6 Gy group were lower at early time points as compared to thermal injury by itself. These data suggest that CRBI delays and exacerbates apoptosis and inflammation in skin as well as increases necrosis thus resulting in delayed wound healing.

Arsenic and fluoride contaminated groundwaters: A review of current technologies for contaminants removal.

Chronic contamination of groundwaters by both arsenic (As) and fluoride (F) is frequently observed around the world, which has severely affected millions of people. Fluoride and As are introduced into groundwaters by several sources such as water-rock interactions, anthropogenic activities, and groundwater recharge. Coexistence of these pollutants can have adverse effects due to synergistic and/or antagonistic mechanisms leading to uncertain and complicated health effects, including cancer. Many developing countries are beset with the problem of F and As laden waters, with no affordable technologies to provide clean water supply. The technologies available for the simultaneous removal are akin to chemical treatment, adsorption and membrane processes. However, the presence of competing ions such as phosphate, silicate, nitrate, chloride, carbonate, and sulfate affect the removal efficiency. Highly efficient, low-cost and sustainable technology which could be used by rural populations is of utmost importance for simultaneous removal of both pollutants. This can be realized by using readily available low cost materials coupled with proper disposal units. Synthesis of inexpensive and highly selective nanoadsorbents or nanofunctionalized membranes is required along with encapsulation units to isolate the toxicant loaded materials to avoid their re-entry in aquifers. A vast number of reviews have been published periodically on removal of As or F alone. However, there is a dearth of literature on the simultaneous removal of both. This review critically analyzes this important issue and considers strategies for their removal and safe disposal.

Zinc oxide nanoparticles prevent the onset of diabetic nephropathy by inhibiting multiple pathways associated with oxidative stress.

BACKGROUND: Zinc deficiency is strongly correlated with prolonged diabetes mellitus and diabetic nephropathy (DN). Previously, glucose-lowering, insulinomimetic, and ß-cell proliferative activities of zinc oxide nanoparticles (ZON) have been reported. Considering these pleiotropic effects, we hypothesized that ZON modulates multiple cellular pathways associated with necroptosis, inflammation, and renal fibrosis, which are involved in progressive loss of renal function. AIM: This study evaluated the effect of ZON on renal function, leading to the alleviation of DN in streptozotocin (STZ)-induced type 1 diabetic Wistar rats and proposed a probable mechanism for its activity. METHODS: Wistar rats (n = 6/group) were used as healthy controls, diabetic controls, diabetic rats treated with ZON (1, 3, and 10 mg/kg), and insulin controls. Urine and serum biochemical parameters, glomerular filtration rate (GFR), and renal histology were also evaluated. Cultured E11 podocytes were evaluated in vitro for markers of oxidative stress, proteins associated with the loss of renal function, and genes associated with renal damage. KEY FINDINGS: STZ-treated rats receiving oral doses of ZON showed enhanced renal function, with no histological alterations in the kidney tissue. ZON inhibited the TGF-ß/Samd3 pathway in renal fibrosis; blocked Ripk1/Ripk3/Mlkl mediated necroptosis and protected against hyperglycemia-induced pyroptosis. In E11 podocytes, ZON reduced oxidative stress under high glucose conditions and retained podocyte-specific proteins. SIGNIFICANCE: A probable mechanism by which ZON prevents DN has been proposed, suggesting its use as a complementary therapeutic agent for the treatment of diabetic complications. To the best of our knowledge, this is the first study to demonstrate the in vitro effects of ZON in cultured podocytes.

Patterns, barriers, and utilization of oral healthcare provided at primary health centers (PHCs) and its association with oral health status among rural population in Rohtak district, Haryana: A household cross-sectional study.

Introduction: Access to oral healthcare is limited in rural areas, resulting in disparities in oral health services. Primary health centers (PHCs) are essential for providing integrated oral healthcare to rural populations. This study examines the patterns, barriers, and utilization of oral healthcare at PHCs in Rohtak district, Haryana. Materials and Methods: In this 6-month household cross-sectional study, data were collected from a sample of 600 participants residing in rural areas under the jurisdiction of three randomly selected PHCs in Rohtak district. The study employed multistage cluster systematic random sampling procedures. Data collection included structured questionnaires and clinical oral examinations following the type-III ADA classification. Participants' oral health status was evaluated using the WHO oral health assessment form for adults (2013). Descriptive and analytical statistics were used for data analysis. Results and Discussion: Dental caries and periodontal diseases were more common in older age groups. Barriers to oral healthcare among the elderly include fear of dental procedures and low dental literacy. Proximity to PHCs influenced dental service utilization, with higher rates among participants living near a PHC, that is, within 5 km of a PHC. Conclusion: Age, gender, proximity to PHCs, household size, and socioeconomic status play crucial roles in the utilization of oral health services among the rural population. Addressing these factors is essential for improving oral healthcare and overcoming barriers. It is crucial to enhance the accessibility, affordability, and availability of oral health services at PHCs to promote better oral health and overall well-being in rural areas.

Development of a high-throughput scale-down model in Ambr® 250 HT for plasmid DNA fermentation processes.

Recent advances in messenger ribonucleic acid (mRNA) vaccines and gene therapy vectors have increased the need for rapid plasmid DNA (pDNA) screening and production within the biopharmaceutical industry. High-throughput (HT) fermentor systems, such as the Ambr® 250 HT, can significantly accelerate process development timelines of pDNA upstream processes compared to traditional bench-scale glass fermentors or small-scale steam-in-place (SIP) fermentors. However, such scale-down models must be qualified to ensure that they are representative of the larger scale process similar to traditional small-scale models. In the current study, we developed a representative scale-down model of a Biostat® D-DCU 30 L pDNA fermentation process in Ambr® 250 HT fermentors using three cell lines producing three different constructs. The Ambr scale-down model provided comparable process performance and pDNA quality as the 30 L SIP fermentation process. In addition, we demonstrated the predictive value of the Ambr model by two-way qualification, first by accurately reproducing the prior trends observed in a 30 L process, followed by predicting new process trends that were then successfully reproduced in the 30 L process. The representative and predictive scale-down Ambr model developed in this study would enable a faster and more efficient approach to strain/clone/host-cell screening, pDNA process development and characterization studies, process scale-up studies, and manufacturing support.

Chronic dietary iron overload affects hepatic iron metabolism and cognitive behavior in Wistar rats.

BACKGROUND: Iron accumulation in organs affects iron metabolism, leading to deleterious effects on the body. Previously, it was studied that high dietary iron in various forms and concentrations influences iron metabolism, resulting in iron accumulation in the liver and spleen and cognitive impairment. However, the actual mechanism and impact of long-term exposure to high dietary iron remain unknown. As a result, we postulated that iron overload caused by chronic exposure to excessive dietary iron supplementation would play a role in iron dyshomeostasis and inflammation in the liver and brain of Wistar rats. METHODS: Animals were segregated into control, low iron (FAC-Ferric Ammonium Citrate 5000 ppm), and high iron dose group (FAC 20,000 ppm). The outcome of dietary iron overload on Wistar rats was evaluated in terms of body weight, biochemical markers, histological examination of liver and brain tissue, and cognitive-behavioral studies. Also, gene expression of rat brain tissue involving iron transporters Dmt1, TfR1, iron storage protein Fpn1, inflammatory markers Nf-kB, Tnf-α, Il-6, and hepcidin was performed. RESULTS: Our data indicate that excess iron supplementation for 30 weeks leads to decreased body weight, increased serum iron levels, and decreased RBC levels in iron fed Wistar rats. Morris water maze (MWM) studies after 30 weeks showed increased escape latency in the high iron dose group compared with the control group. Histological studies of the high iron dose group showed an iron accumulation in the liver and brain loss of cellular architecture, and cellular degeneration was observed. Excess iron treatment showed upregulation of the Dmt1 gene in iron metabolism and a remarkable increase in the Nf-kB gene in rat brain tissue. CONCLUSION: The results show chronic excess iron supplementation leads to iron accumulation in the liver, leading to inflammation in Wistar rats.

Percutaneous Coronary Interventions Using a Ridaforolimus-Eluting Stent in Patients at High Bleeding Risk.

BACKGROUND: Patients treated with percutaneous coronary intervention are often considered to be at a high bleeding risk (HBR). Drug-eluting stents have been shown to be superior to bare-metal stents in patients with HBR, even when patients were given abbreviated periods of dual antiplatelet therapy (DAPT). Short DAPT has not been evaluated with the EluNIR ridaforolimus-eluting stent. The aim of this study was to evaluate the safety and efficacy of a shortened period of DAPT following implantation of the ridaforolimus-eluting stent in patients with HBR. METHODS AND RESULTS: This was a prospective, multicenter, binational, single-arm, open-label trial. Patients were defined as HBR according to the LEADERS-FREE (Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent versus the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk) trial criteria. After percutaneous coronary intervention, DAPT was given for 1 month to patients presenting with stable angina. In patients presenting with an acute coronary syndrome, DAPT was given for 1 to 3 months, at the investigator's discretion. The primary end point was a composite of cardiac death, myocardial infarction, or stent thrombosis up to 1 year (Academic Research Consortium definite and probable). Three hundred fifteen patients undergoing percutaneous coronary intervention were enrolled, and 56.4% presented with acute coronary syndrome; 33.7% were receiving oral anticoagulation. At 1 year, the primary end point occurred in 15 patients (4.9%), meeting the prespecified performance goal of 14.1% (P<0.0001). Stent thrombosis (Academic Research Consortium definite and probable) occurred in 2 patients (0.6%). Bleeding Academic Research Consortium type 3 and 5 bleeding occurred in 6 patients (1.9%). CONCLUSIONS: We observed favorable results in patients with HBR who underwent percutaneous coronary intervention with a ridaforolimus-eluting stent and received shortened DAPT, including a low rate of ischemic events and low rate of stent thrombosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03877848.

Challenges and Outcomes of the First Stem Cell Transplant Program in Tanzania, East Africa.

Introduction: Due to the significant resources involved in creating HSCT programs there is a significant disparity in the availability of this treatment modality between the developed and developing countries. This manuscript details the process and the outcomes of the first HSCT program in East Africa which was started at Muhimbili National Hospital (MNH) in Dar-es-Salaam, Tanzania. Materials and Methods: Information and data were collected on the processes which had been implemented for starting the HSCT program at MNH. The details of the collaborations, training, infrastructure development, and acquisition of the biomedical equipment, as well as the actual process for HSCT, as well as the outcomes of treatment are described. Observations. The project has been detailed in 4 stages for ease of description: Stage 1: Preparatory work which was performed by the Government of Tanzania, as well as the administrators and clinicians from MNH (July 2017-September 2021). Stage 2: Exploratory gap analysis by the teams from MNH and International Haematology Consortium of HCG Hospital, India (HCG-IHC) in October 2021. Stage 3: Activities for closure of gaps (November 2021). Stage 4: Stem Cell Transplantation Camps (November 2021 to March 2022). 11 peripheral blood stem cell transplants were done in two camps, November 2021 (5 patients), and February 2022 (6 patients). 10 patients underwent autologous peripheral blood stem cell transplantation for multiple myeloma and 1 for lymphoma. The median duration of hospital stay was 19 ± 6 days. The median time for neutrophil engraftment, it was on 8.8 ± 0.8 days, and for platelet engraftment was 9.6 ± 2.4 days. Progression-free survival was 100%, and there was no mortality. Conclusion: Commonalities in the socioeconomic challenges in developing countries can be leveraged to create robust HSCT programs in other developing countries.

Effects of combined radiation and burn injury on the renin-angiotensin system.

The renin-angiotensin system (RAS) plays an important role in wound repair; however, little is known pertaining to RAS expression in response to thermal injury and the combination of radiation plus burn injury (CRBI). The purpose of this study was to test the hypothesis that thermal injury modifies expression of RAS components and CRBI delayed this up-regulation of RAS. Skin from uninjured mice was compared with mice receiving local thermal injury or CRBI (injury site). Skin was analyzed for gene and protein expression of RAS components. There was an initial increase in the expression of various components of RAS following thermal injury. However, in the higher CRBI group there is an initial decrease in AT(1b) (vasoconstriction, pro-proliferative), AT(2) (vasodilation, differentiation), and Mas (vasodilation, anti-inflammatory) gene expression. This corresponded with a delay and decrease in AT(1) , AT(2) , and MAS protein expression in fibroblasts and keratinocytes. The reduction in RAS receptor positive fibroblasts and keratinocytes correlated with a reduction in collagen deposition and keratinocyte infiltration into the wounded area resulting in a delay of reepithelialization following CRBI. These data support the hypothesis that delayed wound healing observed in subjects following radiation exposure may be in part due to decreased expression of RAS.

A pH-tuned chitosan-PLGA nanocarrier for fluconazole delivery reduces toxicity and improves efficacy against resistant Candida.

Fluconazole (FLZ) is a broad-spectrum antifungal used against Candida infections. Candida auris displays resistance to FLZ. Drug nanocarriers composed of natural (chitosan, C) or synthetic polymers (polylactide co-glycolide, PLGA) show improved drug characteristics, efficacy and reduction in toxicity. Here, C-PLGA nanoparticles (110 nm) were synthesized by coacervation method and loaded with FLZ, achieving ~8-wt% drug loading. The nanoformulation displayed pH-tuned slow sustained drug release (83 %) up to 5 d, at pH 4, while 34 % release occurred at pH 7.0. Fluorescent-tagged C-PLGA-NPs were localized on the Candida cell wall/membrane as seen by confocal microscopy. This resulted in ~1.9-fold reduced efflux of R6G dye as compared to bare drug treatment in Candida albicans and resistant C. auris. The nanoformulation showed a significant 16- and 64-fold (p < 0.0001) enhanced antifungal activity (MIC 5 and 2.5 µg/ml) against C. albicans and C. auris, respectively, as compared to FLZ. The nanoformulation showed highly effective antifungal activity in-vivo against C. albicans and C. auris. Moreover, the nephrotoxicity and hepatotoxicity was negligible. Thus, PLGA NPs-mediated fluconazole delivery can contribute to increased drug efficacy and to reduce the problem of fungal resistance.

Assessment of Qol among COVID-19 Patients in South India: A Tertiary Care Center Study: An Original Research.

Introduction: The COVID-19 epidemic has brought about an unparalleled health disaster and fundamentally altered people's livelihoods. We intended to examine risk variables for "Health-Related Quality Of Life (HRQoL)" amid COVID-19 hospital discharged patients. Materials and Techniques: For this cross-sectional study, 1000 discharged patients who tested positive at the tertiary care center before January 2022 were included. The HRQoL was measured using a 5-level EuroQoL survey. The complete health state was evaluated using an Indian value set. The correlation of HRQoL and the clinical, sociodemographic parameters were investigated using appropriate statistical tools. Finally, regression model was utilized to identify all factors that predict the HRQoL dimensions. Results: It was found that 55% of patients said they had moderate or serious health issues. Forty percent of respondents said they had felt moderate-to-severe pain or discomfort, compared to 41% who said they had anxiety or sadness. The outcome of the logistic regression demonstrated the substantial influencers were "age, gender, occupation, location of care, heart conditions, and diabetes" on several HRQoL aspects. Conclusion: The COVID-19 dramatically worsens the patients' physical and mental health conditions. Therefore, the government and policymakers must develop comprehensive ways to lessen the patients' mental and physical health problems.

Whole transcriptome sequencing reveals HOXD11-AGAP3, a novel fusion transcript in the Indian acute leukemia cohort.

Introduction: Acute leukemia is a heterogeneous disease with distinct genotypes and complex karyotypes leading to abnormal proliferation of hematopoietic cells. According to GLOBOCAN reports, Asia accounts for 48.6% of leukemia cases, and India reports ~10.2% of all leukemia cases worldwide. Previous studies have shown that the genetic landscape of AML in India is significantly different from that in the western population by WES. Methods: We have sequenced and analyzed 9 acute myeloid leukemia (AML) transcriptome samples in the present study. We performed fusion detection in all the samples and categorized the patients based on cytogenetic abnormalities, followed by a differential expression analysis and WGCNA analysis. Finally, Immune profiles were obtained using CIBERSORTx. Results: We found a novel fusion HOXD11-AGAP3 in 3 patients, BCR-ABL1 in 4, and KMT2A-MLLT3 in one patient. Categorizing the patients based on their cytogenetic abnormalities and performing a differential expression analysis, followed by WGCNA analysis, we observed that in the HOXD11-AGAP3 group, correlated co-expression modules were enriched with genes from pathways like Neutrophil degranulation, Innate Immune system, ECM degradation, and GTP hydrolysis. Additionally, we obtained HOXD11-AGAP3-specific overexpression of chemokines CCL28 and DOCK2. Immune profiling using CIBRSORTx revealed differences in the immune profiles across all the samples. We also observed HOXD11-AGAP3-specific elevated expression of lincRNA HOTAIRM1 and its interacting partner HOXA2. Discussion: The findings highlight population-specific HOXD11-AGAP3, a novel cytogenetic abnormality in AML. The fusion led to alterations in immune system represented by CCL28 and DOCK2 over-expression. Interestingly, in AML, CCL28 is known prognostic marker. Additionally, non-coding signatures (HOTAIRM1) were observed specific to the HOXD11-AGAP3 fusion transcript which are known to be implicated in AML.

Biochemical separation of Cetuximab-Fab from papain-digested antibody fragments and radiolabeling with 64Cu for potential use in radioimmunotheranostics.

Engineered Fab fragments of monoclonal antibodies (mAbs) after radiolabeling with suitable radiometals have the potential to play a key role in personalized radioimmunotheranostics of cancer patients. In this study, we have generated Fab fragment of Cetuximab, a mAb targeting epidermal growth factor receptor (EGFR) expression and purified from the Fc and other fragments by ultrafiltration and affinity chromatography. The Cetuximab-Fab was conjugated with a suitable bifunctional chelator and radiolabeled with no-carrier-added (NCA) 64Cu produced via 64Zn (n, p) 64Cu reaction in a nuclear reactor. The radioimmunoconjugate obtained after size exclusion chromatographic separation possessed >95% radiochemical purity and it retained its integrity over at least three half-lives of the radiometal. Biodistribution studies was performed in fibrosarcoma tumor bearing Swiss mice, which demonstrated the explicit need for purification of the Cetuximab-Fab from Fc fragments. Enhanced and rapid tumor uptake with decent tumor-to-background ratio with prolonged retention was observed when radiolabeled purified Cetuximab-Fab was intravenously administered in animal models. Overall, this preclinical study established the pivotal role of separation science and technology to obtain the radioimmunoconjugate with requisite purity in order to demonstrate optimal pharmacokinetics and maximized treatment efficacy.

Targeted silencing of the MCL-1 gene using multi-layered dendrimer-based nanoconstructs achieves efficient tumor regression in xenografted mice models.

The setback in the practical clinical use of RNA interference (RNAi)-based cancer treatment stems from the lack of targeted small interfering RNA (siRNA) delivery. Here, we show that luteinizing hormone-releasing hormone(LHRH) analog-tethered multi-layered polyamidoamine (PAMAM) nanoconstructs silence the anti-apoptotic MCL-1 gene in LHRH receptor overexpressing human breast (MCF-7) and prostate cancer (LNCaP) cells with 70.91 % and 74.10 % efficiency, respectively. These results were confirmed by RT-PCR. The Acridine orange/Ethidium bromide (AO/EB) dual staining revealed that the silencing of MCL-1 induced apoptosis in both the cell lines. In vivo tumor regression studies performed using MCF-7 and LNCaP xenografted severe combined immunodeficiency(SCID) mice demonstrated highly improved tumor regression in groups treated with targeted nanoconstructs complexed with MCL-1 siRNA (T + siMCL-1) compared to the other treatment groups. The quantitative RT-PCR results of tumor tissues demonstrated significant MCL-1 gene silencing, i.e., 73.76 % and 92.63 % in breast and prostate tumors, respectively, after T + siMCL-1 treatment. Reduction in MCL-1 protein expression as assessed by immunohistochemistry further confirmed these results. Furthermore, the caspase 3/7 assay demonstrated apoptosis in the MCL-1 silenced tissues. The study strongly suggests that targeted delivery of siRNAs using multi-layered dendrimer nanostructures could be an effective therapy for LHRH overexpressing cancers.

Evaluation of randomised controlled trials published in Indian specialty dental journals for statistical testing of baseline differences: A meta-epidemiological study.

Background: In randomised controlled trials (RCTs), the application of a test of significance to compare the baseline differences between the intervention groups is a common practice, though it has been condemned by many researchers. Objective: This study aimed to assess the proportion of RCTs on human participants comparing the baseline differences between intervention groups using the test of significance in nine dental specialty journals published in India and to estimate the proportion of studies reporting baseline demographic and clinical characteristics in a table. Materials and Methods: RCTs published in nine dental journals published by dental specialty associations of India were screened. A literature search was limited to the time duration of five years from 2017 to 2021. Results: The authors analysed 326 RCTs. Of 326 RCTs published, 237 RCTs (72.7%) did not report the baseline demographic and clinical characteristics table. Tests of significance were applied to compare baseline differences between the intervention arms in 148 (45.4%) RCTs published. Conclusions: Although criticised by the Consolidated Standards of Reporting Trials (CONSORT) statement, the majority of the trials published in dental specialty journals failed to avoid comparison of baseline differences with significance test and failed to report baseline characteristic table.