Ponatinib delays the growth of solid tumours by remodelling immunosuppressive tumour microenvironment through the inhibition of induced PD-L1 expression.

BACKGROUND: Therapeutic modalities including chemo, radiation, immunotherapy, etc. induce PD-L1 expression that facilitates the adaptive immune resistance to evade the antitumour immune response. IFN-γ and hypoxia are some of the crucial inducers of PD-L1 expression in tumour and systemic microenvironment which regulate the expression of PD-L1 via various factors including HIF-1α and MAPK signalling. Hence, inhibition of these factors is crucial to regulate the induced PD-L1 expression and to achieve a durable therapeutic outcome by averting the immunosuppression. METHODS: B16-F10 melanoma, 4T1 breast carcinoma, and GL261 glioblastoma murine models were established to investigate the in vivo antitumour efficacy of Ponatinib. Western blot, immunohistochemistry, and ELISA were performed to determine the effect of Ponatinib on the immunomodulation of tumour microenvironment (TME). CTL assay and flow cytometry were such as p-MAPK, p-JNK, p-Erk, and cleaved caspase-3 carried out to evaluate the systemic immunity induced by Ponatinib. RNA sequencing, immunofluorescence and Western blot analysis were used to determine the mechanism of PD-L1 regulation by Ponatinib. Antitumour immunity induced by Ponatinib were compared with Dasatinib. RESULTS: Here, Ponatinib treatment delayed the growth of tumours by inhibiting PD-L1 and modulating TME. It also downregulated the level of PD-L1 downstream signalling molecules. Ponatinib enhanced the CD8 T cell infiltration, regulated Th1/Th2 ratio and depleted tumour associated macrophages (TAMs) in TME. It induced a favourable systemic antitumour immunity by enhancing CD8 T cell population, tumour specific CTL activity, balancing the Th1/Th2 ratio and lowering PD-L1 expression. Ponatinib inhibited FoxP3 expression in tumour and spleen. RNA sequencing data revealed that Ponatinib treatment downregulated the genes related to transcription including HIF-1α. Further mechanistic studies showed that it inhibited the IFN-γ and hypoxia induced PD-L1 expression via regulating HIF-1α. Dasatinib was used as control to prove that Ponatinib induced antitumour immunity is via PD-L1 inhibition mediated T cell activation. CONCLUSIONS: RNA sequencing data along with rigorous in vitro and in vivo studies revealed a novel molecular mechanism by which Ponatinib can inhibit the induced PD-L1 levels via regulating HIF-1α expression which leads to modulation of tumour microenvironment. Thus, our study provides a novel therapeutic insight of Ponatinib for the treatment of solid tumours where it can be used alone or in combination with other drugs which are known to induce PD-L1 expression and generate adaptive resistance.

Genetically Engineered Nanoparticles of Asymmetric Triblock Polypeptide with a Platinum(IV) Cargo Outperforms a Platinum(II) Analog and Free Drug in a Murine Cancer Model.

The development of platinum(Pt)-drugs for cancer therapy has stalled, as no new Pt-drugs have been approved in over a decade. Packaging small molecule drugs into nanoparticles is a way to enhance their therapeutic efficacy. To date, there has been no direct comparison of relative merits of the choice of Pt oxidation state in the same nanoparticle system that would allow its optimal design. To address this lacuna, we designed a recombinant asymmetric triblock polypeptide (ATBP) that self-assembles into rod-shaped micelles and chelates Pt(II) or enables covalent conjugation of Pt(IV) with similar morphology and stability. Both ATBP-Pt(II) and ATBP-Pt(IV) nanoparticles enhanced the half-life of Pt by ∼45-fold, but ATBP-Pt(IV) had superior tumor regression efficacy compared to ATBP-Pt(II) and cisplatin. These results suggest loading Pt(IV) into genetically engineered nanoparticles may yield a new generation of more effective platinum-drug nanoformulations.

A novel, minimally invasive implant to assist in repeated intraocular drug delivery.

The standard of care for posterior segment disorders such as wet age-related macular degeneration, diabetic macular oedema and retinal vascular occlusions is pharmacotherapy by intravitreal drug delivery. Since the therapeutic effect of these drugs lasts only around 4 to 8 weeks, repeated intravitreal injections are required. Pain is experienced by the patients during injection as the needle courses through the sclera and choroid. The current work describes the design and development of a novel anodized titanium alloy implant that allows for intravitreal injections through the implant so that the needle transverses only the conjunctiva, thus minimizing discomfort to the patient. Both ex-vivo testing of the implant in enucleated goat's eye as well as in-vivo validation in rabbit eyes was carried out. The implant was placed through pars plana via a minor surgical procedure and was sutured to the sclera and covered with conjunctiva. Subsequent intravitreal injections were administered under topical anaesthesia with a 30-gauge needle through the implant thus delivering the drug into the vitreous cavity. Repeated intravitreal injections were administered every 2 weeks via the implant for 3 months in 4 rabbits. Apart from cataract in 1 rabbit, no complications were observed. There was no evidence of intra-ocular inflammation or infection at final follow-up. Histopathological analysis did not reveal any inflammation or necrosis around the area of implant. The implants were subsequently removed at 5 months and scleral wound was closed with a single suture. The sclera and overlying conjunctiva healed well and no intraocular complications were observed after removal.

Fabrication of In Situ Layered Hydrogel Scaffold for the Co-delivery of PGDF-BB/Chlorhexidine to Regulate Proinflammatory Cytokines, Growth Factors, and MMP-9 in a Diabetic Skin Defect Albino Rat Model.

Diabetes mellitus (DM)-associated impairments in wound healing include prolonged inflammation, the overexpression of matrix metalloproteases (MMPs), and low levels of growth factors at the wound site. To this end, a layer-by-layer scaffold (SL-B-L) made of cross-linked silk fibroin and hyaluronic acid is developed to deliver chlorhexidine, an antimicrobial agent and an MMP-9 inhibitor, along with the PDGF-BB protein. SL-B-L exhibited highly porous morphology. Diabetic rats treated with SL-B-L demonstrated an early wound closure, a fully reconstructed epithelial layer by 14 days, and reduced levels of IL-6, TNF-α, TGF-ß1, and MMP-9. Interestingly, SL-B-L treatment increased angiogenesis, the bioavailability of collagen, DNA content, and VEGF-A levels. Furthermore, enhanced keratinocyte-fibroblast interaction along with ordered collagen deposition was observed in SL-B-L-treated rats. Most interestingly, when compared with a clinically used scaffold SEESKIN+, SL-B-L outperformed in promoting wound healing in a diabetic rat model by regulating the inflammation while delivering growth factor and the MMP-9 inhibitor.

A comparison of cost and cost-effectiveness analysis of two- implant-retained overdentures versus other removable prosthodontic treatment options for edentulous mandible: A systematic review.

AIM: The aim of this study was to examine systematically the data published on the cost and cost-effectiveness of mandibular two-implant-retained overdentures compared to other removable prosthodontic treatment options for edentulous mandible. SETTINGS AND DESIGN: It is a systematic review which analyses the available data from the prospective and retrospective studies and randomized clinical trials to find out costs and cost effectiveness of different removable treatment modalities for completely edentulous mandible. The study protocol was decided according to PRISMA guidelines. MATERIALS AND METHODS: The search was limited to English literature only and included an electronic search through PubMed Central, Cochrane Central Register of Controlled Trials, and complemented by hand-searching. All clinical trials published up to August 2019 were included (without any starting limit). Two independent investigators extracted the data and assessed the studies. STATISTICAL ANALYSIS USED: No meta-analysis was conducted because of the high heterogeneity of data. RESULTS: Out of the initial 509 records, only nine studies were included. The risks of bias of individual studies were assessed. Six studies presented data on cost and cost analysis only. The rest three articles provided data on cost-effectiveness. The overall costs of implant overdentures were higher than the conventional complete dentures. However, implant overdentures were more cost-effective when compared to conventional complete dentures. Single-implant overdentures are also less expensive than two-implant overdentures. Overdentures supported by two or four mini-implants were also reported as more cost-effective than conventional two-implant-supported overdentures. CONCLUSIONS: Two-implant-retained overdentures are more expensive but cost-effective than the conventional complete dentures. Two- or four-mini-implant-retained overdentures are less expensive than two-implant-retained overdentures, but there is a lack of long-term data on aftercare cost and survival rate of mini-implants. Single-implant overdentures are also less expensive than the two-implant-retained overdentures. The differences of the aftercare costs of different attachment systems for implant overdentures were not significant. There is a need of further studies on comparative cost-effectiveness of different types of implant overdentures.

A study on the accuracy of horizontal condylar guidance values in edentulous patients using preprosthetic diagnostic radiographs.

CONTEXT: Determination of horizontal condylar guidance (HCG) by various clinical and radiographic methods was performed by several investigators. If a correlation between HCG values using lateral radiographic tracing and protrusive interocclusal records can be established, the necessity of performing elaborate recording procedures can be eliminated. AIMS: The aim of this study is to evaluate and to compare the correlation between HCG values in edentulous people using the protrusive interocclusal records mounted on a semi-adjustable articulator with the manual tracing of panoramic radiograph and lateral cephalogram. MATERIALS AND METHODS: A total of 20 completely edentulous individuals of either sex from 45 to 75 years (mean age 63.15 years) fulfilling the inclusion criteria were included in this in vivo study. In all the participants, HCG angles were determined clinically using protrusive interocclusal records and semi-adjustable articulator after intraoral gothic arch tracing. Radiographically, it was obtained by cephalometric tracing of panoramic radiograph and lateral cephalogram. RESULTS: The present study shows mean HCG ± standard deviation (SD) of 28.17° ± 5.99° for interocclusal protrusive record while cephalometric tracing method yielded HCG ± SD of 38.95° ± 4.77° and 35.2° ± 4.94° for lateral cephalogram and orthopantomogram, respectively. A statistically significant positive correlation (P < 0.0001) was found among these three methods. CONCLUSION: HCG can be successfully determined in edentulous participants by using three aforementioned methods. HCG values from cephalometric tracing of diagnostic radiographs can be used as an adjunct to the clinical method but cannot be used independently for programming a semi-adjustable articulator.

A study on the evaluation of bite force, prosthetic and nutritional status in adult cleft patients in Kolkata.

CONTEXT: Altered orofacial morphology and poor dental status affects the dietary intake of cleft patient, making susceptible to nutritional imbalance. Oral health care planning for this population is impossible without the evaluation of stomatognathic functional status as well as prosthetic and nutritional status and need. AIMS: The aim of this study was to evaluate prosthetic status and prosthetic treatment need, bite force and nutritional status, in adult cleft patients and to compare them with the adult noncleft population of similar definition. SETTINGS AND DESIGN: Cleft (n = 250) and noncleft (n = 250) individuals of either sex, aged 18 years or above, excluding severe medically compromised and differently abled, were examined and individual biteforce was measured after obtaining written consent and ethical clearance from the two institutions in Kolkata. SUBJECTS AND METHODS: A "raw data sheet" was prepared according to the parameters of the "Oral Health Surveys: Basic methods," World Health Organization (1997) for evaluation of prosthetic status and need, dentition status and Mini-Nutritional Assessment, Nestlé (1994) for the evaluation nutritional status. A Gnathodynamometer was used to record bite force. STATISTICAL ANALYSIS USED: Statistical analysis was performed using SPSS 20.0.1, Graph Pad Prism version 5, Student's t-test, and Chi-square test. RESULTS: The mean bite force of frontal area in cleft group (3.4356 ± 0.9457 kgf) was found to be significantly lower (P < 0.0001) than in noncleft (22.8749 ± 5.3644 kgf) group. The difference of mean bite force in the right side (2.4576 ± 0.6131 kgf) and left side (1.2708 ± 0.1036 kgf) in cleft group was found to be statistically significant (P < 0.0001). Prosthetic need in maxillary arch was found to be significantly (χ2: 490.0000; P < 0.0001) higher in cleft than in noncleft group. Nutritional status was observed to be significantly (χ2: 179.4049; P < 0.0001) higher "at risk" in cleft than in noncleft group. CONCLUSIONS: Lack of adequate Government concern leading to significantly higher prosthetic need and lower prosthetic status, hence lower bite force resulting lower nutritional status in adult cleft patients in Kolkata.

A comparative analysis of salivary factors and maxillary denture retention in different arch forms: An in vivo study.

AIMS: This study aims to find the effect of change in different salivary factors before and after complete denture insertion and to measure the maxillary denture retention in different arch forms. MATERIALS AND METHODS: Thirty completely edentulous individuals (10 each of square, tapered, and ovoid arch form of maxilla) belonging to the age group of 40-70 years were selected. Salivary factors (flow, density, pH, viscosity, and total protein) were evaluated before and after denture insertion. Retention of maxillary denture was measured in all the different arch forms. STATISTICAL ANALYSIS: Student's independent sample's t-test was applied. The correlation was analyzed by Pearson's correlation analysis. RESULTS: While mean flow rate and pH of saliva increased, mean viscosity, total protein, and density of saliva decreased after maxillary complete denture insertion. A positive correlation was found between retention and total maxillary basal surface area. Retention value was found to be greatest in square type and least in tapered type. CONCLUSIONS: Complete denture acts as a mechanical stimulant thus increasing flow rate and pH immediately after complete denture insertion. Density, total protein, and viscosity of saliva decreased after complete denture insertion which may be due to increase in water content of saliva. The retention of maxillary complete denture does not seem to depend on the rate of change of the salivary factors, before and after complete denture insertion. Total basal surface area and maxillary denture retention values were highest in square arch form and least in tapered arch form.

Encapsulating a Hydrophilic Chemotherapeutic into Rod-like Nanoparticles of a Genetically Encoded Asymmetric Triblock Polypeptide Improves its Efficacy.

Encapsulating hydrophilic chemotherapeutics into the core of polymeric nanoparticles can improve their therapeutic efficacy by increasing their plasma half-life, tumor accumulation and intracellular uptake, and by protecting them from premature degradation. To achieve these goals, we designed a recombinant asymmetric triblock polypeptide (ATBP) that self-assembles into rod-shaped nanoparticles, and which can be used to conjugate diverse hydrophilic molecules, including chemotherapeutics, into their core. These ATBPs consist of three segments: a biodegradable elastin-like polypeptide, a hydrophobic Tyrosine-rich segment, and a short Cysteine-rich segment, that spontaneously self-assemble into rod-shaped micelles. Covalent conjugation of a structurally diverse set of hydrophilic small molecules, including a hydrophilic chemotherapeutic -gemcitabine- to the Cysteine residues also leads to formation of nanoparticles over a range of ATBP concentrations. Gemcitabine-loaded ATBP nanoparticles have significantly better tumor regression compared to free drug in a murine cancer model. This simple strategy of encapsulation of hydrophilic small molecules by conjugation to an ATBP can be used to effectively deliver a range of water-soluble drugs and imaging agents in vivo.

A comparative study to correlate between clinically and radiographically determined sagittal condylar guidance in participants with different skeletal relationships.

CONTEXT: Many authors have conducted studies that determine horizontal condylar guidance (HCG) using various methods, articulator systems, and recording materials. However, there is a dearth of literature on variability existing in HCG in individuals with different skeletal relationships. This study is an attempt to verify whether such a difference exists or not. AIMS: The aim of this study is to determine and correlate the HCG in individuals with Angle's Class I, Class II, and Class III malocclusion using radiographic and clinical methods. SETTINGS AND DESIGN: HCG was recorded for thirty individuals, ten of each class. For each individual, HCG was recorded clinically as well as radiographically. SUBJECTS AND METHODS: Clinically, HCG was recorded using protrusive check bites and a semi-adjustable articulator. Radiographically, two methods were employed. First, a "tangent method" wherein the angle made by a tangent to the posterior slope of articular eminence with the Frankfurt horizontal (FH) plane was considered as the HCG, and second, a "protrusive method" where the position of the condyle at maximum intercuspation and 6 mm protrusion were traced, and the angle this path made with the FH plane was recorded as the HCG. STATISTICAL ANALYSIS: Descriptive statistical analysis along with Tukey's test and analysis of variance was used to calculate and compare the mean values. Pearson correlation coefficient was used to establish correlation between various means. RESULTS: A significant difference in the HCG of three skeletal relationships was seen, with Class II having a steeper angle than the other two. Among the various methods used, a correlation was found between the clinical and the protrusive method; however, the tangent method yielded greater values of HCG. CONCLUSIONS: The average value of HCG should not be used as it differs according to the skeletal relationship. Radiographic method can be used to yield consistent HCG; however, the protrusive method should be employed.

Use of digital panoramic radiology in presurgical implant treatment planning to accurately assess bone density.

STATEMENT OF PROBLEM: No cost-effective method of ascertaining bone density from 2-dimensional radiographic images is currently available for dental implants before surgery. PURPOSE: The purpose of this in vivo study was to use digital panoramic radiology and dental computed tomography (CT) to evaluate the bone density of specific points in the jaw near the tooth-bearing areas. The objective was to determine whether digital panoramic radiology can be used in assessing bone density as an alternative to a more expensive and complex dental CT. MATERIAL AND METHODS: This study involved determining bone densities at predetermined anatomic landmarks near tooth-bearing areas of the jaws of 20 participants, using digital panoramic radiology in gray-level scale with a lead step wedge. Subsequently, the bone densities of the same points were determined in Hounsfield units (Hu) with dental CT. The data collected after interpretation of the panoramic radiograph and CT were tabulated and analyzed statistically. RESULTS: Bone density measured using CT correlated with the first 3 steps of (A, B, and C) the digital scale of gray. Further analysis conducted using the Mann-Whitney U test showed a significant association between step A to detect D4 bone, step B to detect D3 bone, and step C to detect D2 type bone. CONCLUSIONS: The digital scale of gray obtained from a lead step wedge can be effectively used with digital orthopanoramic radiology to assess bone density before the placement of implants, but with certain restrictions.

A noncanonical function of sortase enables site-specific conjugation of small molecules to lysine residues in proteins.

We provide the first demonstration that isopeptide ligation, a noncanonical activity of the enzyme sortase A, can be used to modify recombinant proteins. This reaction was used in vitro to conjugate small molecules to a peptide, an engineered targeting protein, and a full-length monoclonal antibody with an exquisite level of control over the site of conjugation. Attachment to the protein substrate occurred exclusively through isopeptide bonds at a lysine ε-amino group within a specific amino acid sequence. This reaction allows more than one molecule to be site-specifically conjugated to a protein at internal sites, thereby overcoming significant limitations of the canonical native peptide ligation reaction catalyzed by sortase A. Our method provides a unique chemical ligation procedure that is orthogonal to existing methods, supplying a new method to site-specifically modify lysine residues that will be a valuable addition to the protein conjugation toolbox.

Ring-opening polymerization of prodrugs: a versatile approach to prepare well-defined drug-loaded nanoparticles.

The synthesis of polymer-drug conjugates from prodrug monomers consisting of a cyclic polymerizable group that is appended to a drug through a cleavable linker is achieved by organocatalyzed ring-opening polymerization. The monomers polymerize into well-defined polymer prodrugs that are designed to self-assemble into nanoparticles and release the drug in response to a physiologically relevant stimulus. This method is compatible with structurally diverse drugs and allows different drugs to be copolymerized with quantitative conversion of the monomers. The drug loading can be controlled by adjusting the monomer(s)/initiator feed ratio and drug release can be encoded into the polymer by the choice of linker. Initiating these monomers from a poly(ethylene glycol) macroinitiator results in amphiphilic diblock copolymers that spontaneously self-assemble into micelles with a long plasma circulation, which is useful for systemic therapy.

Comparative evaluation of bond strength of all-metal crowns with different luting agents after undergoing various modes of surface treatments: An in-vitro study.

AIM: This study includes a comparative evaluation of the various surface treatments of the intaglio surface of crowns in combination with various luting agents for maximal retention. MATERIALS AND METHODS: Totally, 150 dies of a standard complete crown preparation were fabricated. Wax pattern with a loop on the occlusal surface was prepared on each die using standard procedures, and then crowns were cast with nickel-chromium alloy. These crowns were randomly divided into five groups as per the surface of the intaglio surface of the metal copings. The crowns in each group were again subdivided randomly into three groups as per the luting agents used resin-modified glass ionomer cement, glass ionomer cement, and zinc phosphate cement. Retention was measured (MPa) by separating the metal crowns from the metallic die under tension on a Universal testing machine. STATISTICAL ANALYSIS USED: The data were recorded and statistically analyzed using one-way analysis of variance followed by Tukey's test. RESULTS: The retention differed both with surface treatment and type of luting agents. Untreated group showed the least bond strengths < sandblasting with 50 µm alumina < sandblasting with 50 µm alumina with ultrasonic cleaning < sandblasting with 110 µm alumina < sandblasting with 110 µm alumina along with ultrasonic cleaning. For luting agents, glass ionomer cement showed least bond strength because there was no chemical bonding present between metal crown and metallic die, followed by zinc phosphate cement and maximum bond strength were found for resin-modified glass ionomer cement. CONCLUSION: Among all types of surface treatments used in this study, maximum bond strength was yielded by sandblasting with 110 µm alumina + ultrasonic cleaning and the best luting agent was resin-modified glass ionomer cement.

iTEP nanoparticle-delivered salinomycin displays an enhanced toxicity to cancer stem cells in orthotopic breast tumors.

Salinomycin (Sali) has selective toxicity to cancer stem cells (CSCs), a subpopulation of cancer cells that have been recently linked with tumor multidrug resistance (MDR). To utilize its selective toxicity for cancer therapy, we sought to devise a nanoparticle (NP) carrier to deliver Sali to solid tumors through the enhanced permeability and retention effect and, hence, to increase its exposure to CSCs. First, hydrophobic Sali was conjugated to a hydrophilic, immune-tolerant, elastin-like polypeptide (iTEP); the amphiphilic iTEP-Sali conjugates self-assemble into NPs. Next, free Sali was encapsulated into the NPs alone or with two additives, N,N-dimethylhexylamine (DMHA) and α-tocopherol. The coencapsulation significantly improved the loading efficiency and release profile of Sali. The resulting NPs of the coencapsulation, termed as iTEP-Sali NP3s, have an in vitro release half-life of 4.1 h, four times longer than iTEP-Sali NP2s, the NPs that have encapsulated Sali only. Further, the NP3 formulation increases the plasma area under curve and the tumor accumulation of Sali by 10 and 2.4 times, respectively. Lastly, these improved pharmacokinetic and tumor accumulation profiles are consistent with a boost of CSC-elimination effect of Sali in vivo. In NP3-treated 4T1 orthotopic tumors, the mean CSC frequency is 55.62%, a significant reduction from the mean frequencies of untreated tumors, 75.00%, or free Sali-treated tumors, 64.32%. The CSC-elimination effect of the NP3 can further translate to a delay of tumor growth. Given the role of CSCs in driving tumor MDR and recurrence, it could be a promising strategy to add the NP3 to conventional cancer chemotherapies to prevent or reverse the MDR.

Investigation into the effect of use of metal primer on adhesion of heat cure acrylic resin to cast titanium: an in vitro study.

The availability of adhesive primers capable of bonding chemically to base metal alloys without well defined passive oxide surface film has been improved significantly over the last decade. Therefore, the purpose of the study was to compare and evaluate the effect of metal primer on adhesion of heat cure acrylic resin to cast titanium. Shear bond strength test was conducted on 80 commercially pure titanium cast metal heat-cure acrylic resin discs treated with different surface treatments. The first group received no surface treatment (group I); the second group was subjected to sandblasting (group II); the third group was treated with bonding agent (alloy primer) (group III) and the fourth was treated with sandblasting and alloy primer (group IV). After the samples were surface treated, acrylic resin was mixed, packed and processed over the test area of cast titanium. Ten specimens of each group were immersed in distilled water for 24 h followed by thermocycling for 20,000 cycles. Shear bond-strength between the heat cure acrylic resin and titanium was evaluated using Instron universal testing machine. Debonded specimens of all the groups were subjected to SEM analysis. The bond failure (MPa) was analyzed by ANOVA and Duncan's multiple comparison tests. Surface treatment with sandblasting, followed by the application of alloy primer showed maximum shear bond strength before and after thermocycling (24.50 ± 0.59 and 17.39 ± 1.56 MPa respectively).The bond strength values are found to be in decreasing magnitudes as group IV > group III > group II > group I. The following pretreatment to improve the shear bond strength of heat cure acrylic resin to titanium is recommended in order to attain the maximum bond strength in cast titanium frameworks for various prostheses: sandblasting, cleaning in an ultrasonic bath for 10 min and air drying followed by application of a bonding agent uniformly on the sandblasted cast titanium surface before packing with heat cure acrylic resin.

Gut microbiota and epigenetics in colorectal cancer: implications for carcinogenesis and therapeutic intervention.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The occurrence of CRC is associated with various genetic and epigenetic mutations in intestinal epithelial cells that transform them into adenocarcinomas. There is increasing evidence indicating the gut microbiota plays a crucial role in the regulation of host physiological processes. Alterations in gut microbiota composition are responsible for initiating carcinogenesis through diverse epigenetic modifications, including histone modifications, ncRNAs and DNA methylation. This work was designed to comprehensively review recent findings to provide insight into the associations between the gut microbiota and CRC at an epigenetic level. These scientific insights can be used in the future to develop effective strategies for early detection and treatment of CRC.

Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide. It happens when certain changes occur in the cells lining the intestine, turning them into cancerous growths. Recent studies suggest the collection of microbes in our gut, called the gut microbiota, plays a big role in how our body works. Dysregulation in gut microbiota composition is responsible for the development of colorectal cancer. This work provides a closer look at these recent discoveries to better understand how gut microbes might influence the development of colorectal cancer by affecting gene function. Understanding this connection may facilitate early diagnosis and treatment of colorectal cancer.

Encapsulation of telmisartan inside insulinoma-cell-derived extracellular vesicles outperformed biomimetic nanovesicles in modulating the pancreatic inflammatory microenvironment.

Diabetes mellitus (DM) is a chronic metabolic condition, characterized by hyperglycaemia, oxidative imbalance, pancreatic ß-cell death, and insulin insufficiency. Angiotensin II (Ang II) increases oxidative stress, inflammation, and apoptosis, and Ang II type 1 receptor (AT1R) blockers (ARBs) can ameliorate inflammatory response and oxidative stress. However, like other small-molecule drugs, free ARBs show poor in vivo efficacy and dose-limiting toxicities. Hence, in this study, we developed nano-formulations of telmisartan (TEL), an ARB, by encapsulating it inside a murine insulinoma cell-derived extracellular vesicle (nanoTEL) and a bio-mimetic lipid nanovesicle (lipoTEL). Both nano-formulations showed spherical morphology and sustained release of TEL. In vitro, nanoTEL restored oxidative equilibrium, attenuated reactive oxygen species levels, enhanced the uptake of glucose analogue, and increased the expression of glucose transporter protein 4 better than lipoTEL. In a streptozotocin-induced murine model of diabetes, nanoTEL lowered blood glucose levels, improved glucose tolerance, and promoted insulin synthesis and secretion significantly better than lipoTEL. Moreover, nanoTEL was found superior in ameliorating the pancreatic inflammatory microenvironment by regulating NF-κBp65, HIF-1α, and PPAR-γ expression; modulating IL-1ß, IL-6, tumor necrosis factor-α, IL-10, and IL-4 levels and inducing the polarization of macrophage from M1 to M2. Further, nanoTEL administration induced angiogenesis and promoted the proliferation of pancreatic cells to restore the structural integrity of the islets of Langerhans more efficiently than lipoTEL. These findings collectively suggest that nanoTEL outperforms lipoTEL in restoring the function of pancreatic ß-cells by modulating the pancreatic inflammatory microenvironment and show potential for the treatment of DM.

Alleviating hypoxia and oxidative stress for treatment of cardiovascular diseases: a biomaterials perspective.

A state of hypoxia (lack of oxygen) persists in the initial and later phases of healing in cardiovascular diseases, which can alter the tissue's repair or regeneration, ultimately affecting the structure and functionality of the related organ. Consequently, this results in a cascade of events, leading to metabolic stress and the production of reactive oxygen species (ROS) and autophagy. This unwanted situation not only limits the oxygen supply to the needy tissues but also creates an inflammatory state, limiting the exchange of nutrients and other supplements. Consequently, biomaterials have gained considerable attention to alleviate hypoxia and oxidative stress in cardiovascular diseases. Numerous oxygen releasing and antioxidant biomaterials have been developed and proven to alleviate hypoxia and oxidative stress. This review article summarizes the mechanisms involved in cardiovascular pathologies due to hypoxia and oxidative stress, as well as the treatment modalities currently in practice. The applications, benefits and possible shortcomings of these approaches have been discussed. Additionally, the review explores the role of novel biomaterials in combating the limitations of existing approaches, primarily focusing on the development of oxygen-releasing and antioxidant biomaterials for cardiac repair and regeneration. It also directs attention to various other potential applications with critical insights for further advancement in this area.

CD40 agonist engineered immunosomes modulated tumor microenvironment and showed pro-immunogenic response, reduced toxicity, and tumor free survival in mice bearing glioblastoma.

CD40 agonist antibodies (αCD40) have shown promising anti-tumor response in both preclinical and early clinical studies. However, its systemic administration is associated with immune- and hepato-toxicities which hampers its clinical usage. In addition, αCD40 showed low tumor retention and induced PD-L1 expression which makes tumor microenvironment (TME) immunosuppressive. To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it. Immunosomes showed higher tumor accumulation till 96 h of administration and displayed sustained release of αCD40 in vivo. Immunosomes significantly delayed tumor growth and showed tumor free survival in mice bearing GL-261 glioblastoma by increasing the population of CD45+CD8+ T cells, CD45+CD20+ B cells, CD45+CD11c+ DCs and F4/80+CD86+ cells in TME. Immunosome significantly reduced the population of T-regulatory cells, M2 macrophage, and MDSCs and lowered the PD-L1 expression. Moreover, Immunosomes significantly enhanced the levels of Th1 cytokines (IFN-γ, IL-6, IL-2) over Th2 cytokines (IL-4 and IL-10) which supported anti-tumor response. Most interestingly, Immunosomes averted the in vivo toxicities associated with free αCD40 by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-1α and reduced the degree of liver damage. In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.