Dissecting the Impact of the Gut Microbiome on Cancer Immunotherapy.

The gut microbiome has emerged as a key regulator of response to cancer immunotherapy. However, there is a gap in our understanding of the underlying mechanisms by which the microbiome influences immunotherapy. To this end, we developed a mathematical model based on i) gut microbiome data derived from preclinical studies on melanomas after fecal microbiota transplant, ii) mechanistic modeling of antitumor immune response, and iii) robust association analysis of murine and human microbiome profiles with model-predicted immune profiles.

Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma.

Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.

Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use.

A facile magnetic extrusion method for preparing endosome-derived vesicles for cancer drug delivery.

To date, the scaled-up manufacturing and efficient drug loading of exosomes are two existing challenges limiting the clinical translation of exosome-based drug delivery. Herein, we developed a facile magnetic extrusion method for preparing endosome-derived vesicles, also known as exosome mimetics (EMs), which share the same biological origin and similar morphology, composition, and biofunctions with native exosomes. The high yield and consistency of this magnetic extrusion method help to overcome the manufacturing bottleneck in exosome research.

Hallmarks of response, resistance, and toxicity to immune checkpoint blockade.

Unprecedented advances have been made in cancer treatment with the use of immune checkpoint blockade (ICB). However, responses are limited to a subset of patients, and immune-related adverse events (irAEs) can be problematic, requiring treatment discontinuation. Iterative insights into factors intrinsic and extrinsic to the host that impact ICB response and toxicity are critically needed.

The role of extracellular vesicles in the physiological and pathological regulation of the blood-brain barrier.

Extracellular vesicles (EVs) are a subclass of biological nanoparticles secreted by most cell types. Once secreted, EVs can travel long distances to deliver their content to target cells thereby playing a key role in cell-to-cell communication and supporting both physiological and pathological processes. In recent years, the functional versatility of EVs has come to be more widely appreciated.

Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade.

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models.

Platelet-derived extracellular vesicles infiltrate and modify the bone marrow during inflammation.

During inflammation, steady-state hematopoiesis switches to emergency hematopoiesis to repopulate myeloid cells, with a bias toward the megakaryocytic lineage. Soluble inflammatory cues are thought to be largely responsible for these alterations. However, how these plasma factors rapidly alter the bone marrow (BM) is not understood.

Cdc42-Dependent Transfer of mir301 from Breast Cancer-Derived Extracellular Vesicles Regulates the Matrix Modulating Ability of Astrocytes at the Blood-Brain Barrier.

Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood-brain barrier (BBB) via transcytosis and can promote brain metastasis.

Tumor-Derived Extracellular Vesicles Breach the Intact Blood-Brain Barrier Transcytosis.

The restrictive nature of the blood-brain barrier (BBB) creates a major challenge for brain drug delivery with current nanomedicines lacking the ability to cross the BBB. Extracellular vesicles (EVs) have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer and have been suggested as promising therapeutics and drug delivery vehicles. However, the ability of native tumor-derived EVs to breach the BBB and the mechanism(s) involved in this process remain unknown.

Brainwashed by extracellular vesicles: the role of extracellular vesicles in primary and metastatic brain tumour microenvironment.

Brain malignancies, including primary and metastatic brain tumours, are often associated with high mortality, reflecting a need for more effective diagnostics and therapeutics. Despite the different cells of origin, primary and metastatic brain tumours share the same microenvironment, which affects the survival mechanisms adopted by these tumours. Elucidating the mechanisms by which primary and metastatic brain tumours interact with the brain microenvironment can uncover potential targets for clinical applications.

Metalloproteinases and their roles in human cancer.

It is now widely appreciated that members of the matrix metalloproteinase (MMP) family of enzymes play a key role in cancer development and progression along with many of the hallmarks associated with them. The activity of these enzymes has been directly implicated in extracellular matrix remodeling, the processing of growth factors and receptors, the modulation of cell migration, proliferation, and invasion, the epithelial to mesenchymal transition, the regulation of immune responses, and the control of angiogenesis. Certain MMP family members have been validated as biomarkers of a variety of human cancers including those of the breast, brain, pancreas, prostate, ovary, and others.

Accuracy and reliability of cone beam computed tomographic measurements of the bone labial and palatal to the maxillary anterior teeth.

Purpose: The aim of this study was to measure the thickness of bone labial and palatal to maxillary anterior teeth on cone beam computed tomographic (CBCT) images and to compare these measurements with direct clinical measurements to determine the reliability and accuracy of CBCT.

Materials And Methods: Eighteen healthy subjects were randomly selected from among candidates for immediate implant placement in the anterior maxilla. After extraction, labial bone thickness was measured at 1, 4, and 8 mm from the bone crest.

Thickness of labial alveolar bone overlying healthy maxillary and mandibular anterior teeth.

Aim: This study aimed to measure the thickness of labial bone overlying maxillary and mandibular anterior teeth and the distance between cementoenamel junction and bone crest in a Persian population.

Materials & Methods: Two calibrated examiners evaluated tomographic data of 152 maxillary and 200 mandibular anterior teeth. Labial bone width was assessed at levels 1.

Craniofacial morphologic parameters in a Persian population: an anthropometric study.

Limited data are available regarding the reference ranges of facial proportions of the Persian population in Iran. This study aimed to establish the reference range of craniofacial anthropometric measurements in an adult Iranian population. On 100 individuals (men = women), aged 18 to 30 years with normal faces and occlusions, 34 linear and 7 angular measurements as well as 24 indices were calculated.

Stabilization of premaxilla repositioned during secondary bone grafting in complete bilateral cleft lip and palate patients.

Secondary bone grafting simultaneous to premaxillary repositioning is a well-recognized surgical procedure for the management of bilateral cleft lip and palate patients. Proper stabilization of the repositioned premaxilla is considered as a key factor for the success of secondary bone grafting because the mobility of the premaxillary segment jeopardizes graft integration. This case series reports a reliable method of premaxillary stabilization that incorporated the intrasurgical application of resin bone cement to cover and reinforce the arch bars or orthodontic brackets applied on the maxillary teeth.

The osteoregenerative effects of platelet-derived growth factor BB cotransplanted with mesenchymal stem cells, loaded on freeze-dried mineral bone block: a pilot study in dog mandible.

Due to shortcomings associated with autogenous bone graft, the gold standard of craniofacial grafting, investigators seek alternatives that are accessible, efficient, and affordable. Accordingly, in the present pilot study, bone regeneration was induced using bone marrow-derived mesenchymal stem cells (BMSCs) loaded onto freeze-dried mineral bone block (FDMBB) in the presence or absence of recombinant platelet-derived growth factor-BB (rh PDGF-BB). Eight weeks after the bilateral extraction of premolars of four mongrel dogs, 25 × 10 mm defects were created at both sides of the mandible.

Osteoblastic differentiation of human stem cells derived from bone marrow and periodontal ligament under the effect of enamel matrix derivative and transforming growth factor-beta.

Purpose: To increase the understanding of the applicability of biomaterials and growth factors in enhancing stem cell-based bone regeneration modalities, this study evaluated the effects of enamel matrix derivative (EMD) and recombinant human transforming growth factor-beta (rhTGF-β) on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) as well as human periodontal ligament stem cells (hPDLSCs).

Materials And Methods: hBMSCs and hPDLSCs were obtained, and identification of stem cell surface markers was performed according to the criteria of the International Society for Cellular Therapy. Each group of stem cells was separately treated with a serial dilution of EMD (10, 50, and 100 μg/mL) or rhTGF-β (10 ng/mL).

Cortical tenting technique versus onlay layered technique for vertical augmentation of atrophic posterior mandibles: a split-mouth pilot study.

Purpose: This study intended to compare the efficacy of onlay layered and cortical tenting grafting techniques for vertical alveolar augmentation.

Materials And Methods: Six patients with bilaterally edentulous atrophic posterior mandibles received 2 thin ramus blocks, covered with bovine bone mineral on 1 side (onlay layered technique), whereas in the opposite side (cortical tenting technique), a thin ramus block was placed over the ridge keeping a distance that was filled with particulate autogenous bone and bovine bone mineral (50:50). Bone height over the mandibular canal was measured on panoramic radiographies taken preoperatively, and 2 weeks and 4 months postoperatively.

Dental pulp stem cells for in vivo bone regeneration: a systematic review of literature.

Objective: This review of literature was aimed to assess in vivo experiments which have evaluated the efficacy of dental pulp stem cells (DPSCs) for bone regeneration.

Design: An electronic search of English-language papers was conducted on PubMed database. Studies that assessed the use of DPSCs in bone regeneration in vivo were included and experiments evaluating regeneration of hard tissues other than bone were excluded.

The effect of stress on salivary metal ion content in orthodontic patients.

Psychological stress can alter the environment in favor of corrosion of orthodontic alloys by changing the properties of saliva. This study aimed to assess the effect of stress induction on salivary nickel and chromium content in fixed orthodontic patients. Thirty patients were enrolled in this experiment.