Local Proliferation Research Articles

Medullary Solitary Plasmacytoma of Maxilla- A Rare Case Report

Solitary Plasmacytoma (SP) is a rare disease characterized by a localized proliferation of neoplastic monoclonal plasma cells, without evidence of systemic disease. The aetiology of SP remains unknown, but chronic stimulation, overdose irradiation, viruses, and gene interactions in the reticuloendothelial system have been suggested as the etiologic factor. While pain is the most common symptom of osseous mandible SP, it is usually painless in the maxilla and may manifest orally with paresthesia, swelling, soft tissue masses, mobility and migration of teeth, haemorrhage, or pathologic fracture due to cortical destruction of bone. Because the amount of haemopoitic bone marrow in the maxilla is decreased, oral involvement of the maxilla is less common than that of the mandible. A 46-year-old male patient presented with the chief complaint of mobility of his upper left back teeth and swelling over his left-side palatal area. Clinical examination was suggestive of benign odontogenic tumors and salivary gland tumors, while two-dimensional (2D) and three-dimensional (3D) imaging were suggestive of malignant tumors arising from either alveolar bone or maxillary sinus. The laboratory investigations and biopsy revealed solitary plasmacytoma of maxilla. There were clinical symptoms of paresthesia and mobility, but no other signs of malignancy were observed. As the case report concludes, all necessary investigations need to be conducted to exclude all other pathologies, so that treatment can begin as soon as possible.

Curcumol Attenuates Endometriosis by Inhibiting the JAK2/STAT3 Signaling Pathway.

BackgroundCurcumol is a hydrogenated austenitic compound with hemiketal. In this study we evaluated the effects of curcumol on local inflammatory response, cell proliferation, and metastasis in endometriosis, and elucidated the underlying mechanisms.Material/MethodsEctopic endometrial stromal cells were treated with increasing doses of curcumol. The MTT assay was used to assess cell viability. FITC-labeled annexin-V/PI double-staining method and flow cytometry were used to determine cell apoptosis. Cell migration was evaluated using a wound healing assay. ELISA kits were used to detect the levels of TNF-α, IL-6, and IL-1β. Western blot assay was used to examine the phosphorylation degree of JAK2 and STAT3 and the expression of Bax, Bcl2, and caspase-3 proteins. Autologous endometrial transplantation was used to establish a rat model to assess the anti-EMS effect of curcumol in vivo.ResultsCurcumol can inhibit the proliferation of ectopic endometrial stromal cells, promote cell apoptosis, and weaken cell migration ability. Curcumol can reduce the expression of Bax and caspase-3 protein and increase the expression of Bcl2 protein. Curcumol also can inhibit the secretion of inflammatory cytokines, including tumor necrosis cytokines (TNF)-α, interleukin (IL)-6, and IL-1β, by ectopic endometrial stromal cells. In addition, curcumol can also inhibit the phosphorylation of JAK2 and STAT3. In vivo experiments also proved that curcumol could inhibit the growth of ectopic lesions in EMS model rats.ConclusionsCurcumol can inhibit the JAK2/STAT3 pathway, reduce the inflammatory cytokines secreted by ectopic endometrial stromal cells, inhibit cell proliferation and migration, and reduce the volume of ectopic lesions.

Abstract IAP0301: Bispecific T cell engagers (TCEs) for treatment of solid tumors: Challenges and opportunities

Abstract T cell-engaging bispecific antibody constructs (TCEs) have the potential to engage all cytotoxic T cells for redirected cancer cell lysis, including CD8, CD4, gamma/delta, NKT and regulatory T cells. TCEs transiently connect T cells with target cells leading to formation of a cytolytic synapse. Once activated by TCEs, T cells can adopt a serial lysis mode and increase troop size by their local proliferation. In numerous animal models, TCEs can eradicate large tumors as single-agent therapy. TCEs show a remarkable single-agent activity in hematological diseases, including ALL, NHL (DLBCL and FL) and AML. A CD19/CD3-bispecific TCE called blinatumomab (Blincyto) has been approved in 2014, and six other TCEs targeting CD20, BCMA and CD123 are in late-stage development. With complete response rates >50% and durability of responses, TCEs are in par with autologous CD19 CAR-T cells in NHL but are easier to manufacture and allow for a faster treatment start. Treatment of solid tumor indications with TCEs is not as successful as treatment of blood-borne cancers. This may be due to issues with tumor penetration, the hostile tumor microenvironment and the scarcity of T cells in cold tumors. A variety of TCEs explore their single-agent activity against solid tumors by targeting surface antigen like PSMA, GPC3, GD2, or HER-2. Enhancements in the form of combination therapy with checkpoint inhibitors, or 4-1BB and CD28 agonists are being explored as ways of augmenting solid tumor activity of TCEs. The first TCE showing robust anti-tumor activity in a solid tumor indication is targeting a gp100 peptide/MHC (developed by Immunocore). It is made from a soluble TCR fragment of very high affinity for the gp100 peptide HLA*0201 complex fused to an anti-CD3 scFv fragment. Although only few partial responses were observed in uveal melanoma patients, the single-agent treatment showed a very robust improvement in overall survival with a hazard ratio of 0.51 compared to investigators’ choice. This data will inspire the development of more TCEs that are specific for peptide/MHC complexes. This class of targets can also be addresses by TCR-mimetic antibodies. TCEs using such antibodies showed high anti-tumor activity in mouse models against MAGE-A4, p53 mutant or tyrosinase peptide/MHC complexes, all targets that are otherwise not amenable to classical TCEs. Another emerging opportunity for treating cancers are conditional TCEs. These are infused as inactive precursors. Inside tumors, the locally produced proteases convert the precursors into highly active TCEs. One example is the so called ProTriTACs, where a half-life extending albumin-binding domain masks the CD3-binding domain. The mask confers a 500-fold reduction in the cytolytic activity of the TCE. Inside tumors, the mask is cleaved off and a TCE is activated that has a very short serum half-life once it is released from the tumor. Conditional TCEs promise not only a wider therapeutic index but can also leverage as targets tumor-associated antigens that are widely expressed on tumors but also on healthy normal tissues, such as EGFR or EpCAM/TROP1. On-target toxicity of TCEs relates to the quality of target antigens. Finding more tumor-specific surface antigens, appropriate pMHC targets (e.g., mutant oncogene epitopes) and conditional T cell engagers are ways to address this challenge. Off-target toxicity of TCEs relates to T cell activation because of redirected target cell lysis. In the worst case, a cytokine release syndrome is induced. In the best case, a low-level cytokine release is contributing to the efficacy of TCEs. CRS can be managed by steroids, step dosing, anti-IL6 antibody and/or dasatinib. Another promising means is subcutaneous administration of TCEs. A dozen TCE programs currently explore this route, which allows reduction of Cmax and of the initial cytokine release. TCEs will soon become a major weapon in the arsenal of cancer therapy. They will not only work in blood-borne cancers but will soon conquer select solid tumor indications. Peptide/MHC-targeting and conditional TCEs are very promising approaches to achieve solid tumor activity of TCEs. Citation Format: Patrick A. Baeuerle. Bispecific T cell engagers (TCEs) for treatment of solid tumors: Challenges and opportunities [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr IAP0301.

Gastric antral web

Gastric antral web is a rare cause of gastric outlet obstruction with an incidence of 1 in 100,00 births. Only about 150 cases have been reported. Antral web is a thin fenestrated diaphragm made up of 2 layers of mucosa and usually lacking muscular component. Evidence of it being both of congenital or acquired cause has been reported, but the theory of localized endodermal proliferation during developmental stage is the most accepted. The most common presentation is of non-bilious vomiting and often diagnosed in infancy however diagnosis can be delayed due to non obstructive nature of symptoms. It is often misdiagnosed as infantile hypertrophic pyloric stenosis or pylorospasm. It can be confirmed with Barium enhanced radiographs of upper GIT, ultrasound and endoscopy. The non symptomatic antral web can be advised supportive measures but in the symptomatic group surgery is the treatment of choice. Antral web excision with or without pyloroplasty is done. It has good prognosis. • Gastric antral web is a rare cause of gastric outlet obstruction with an incidence of 1 in 100,00 births. • It most commonly presents as non-bilious vomiting and often diagnosed in infancy however its diagnosis can be delayed due to non-obstructive nature of symptoms. • It is often misdiagnosed as infantile hypertrophic pyloric stenosis. • It can be confirmed with Barium enhanced radiographs of upper GIT, ultrasound and endoscopy.

Immunohistochemical Analysis of the Expression of the Glycodelin Cytokine in Endometrial Tissue and the Endometrial Polyp, Before and After Hysteroscopy, in Infertile Female Patients

Abstract An endometrial polyp is most commonly a benign, localized proliferation of the glands and the endometrial stroma, covered with epithelium and protruding above the level of the mucosa. These polyps are most often diagnosed during investigation into the causes of irregular menstrual bleeding or infertility. It is produced in the highest concentration during the secretory phase of the endometrial cycle. The level of glycodelin reaches its peak 12 days after ovulation. The aim of this paper was to determine the changes in the immunohistochemical expression of glycodelin at the level of the endometrium and in the tissue of the polyp, before and after hysteroscopic polypectomy, in infertile female patients with an endometrial polyp, and in the endometrial tissue of female patients without an endometrial polyp. The study included 82 infertile female patients. The infertile patients were divided into two groups. The first was the experimental group which included 56 infertile female patients who had an endometrial polyp. The second group was the control group, composed of 26 infertile female patients who did not have an endometrial polyp. The results obtained primarily indicate the existence of changes in the immunohistochemical expression of the cytokine glycodelin in the female patients from both the experimental and the control group, not only prior to but also after hysteroscopy. A larger number of patients who have an endometrial polyp show a lack of glycodelin expression, more pronouncedly so in the bioptate of the endometrium than in the endometrial polyp.

Bone Marrow-Derived Alk1 Mutant Endothelial Cells and Clonally Expanded Somatic Alk1 Mutant Endothelial Cells Contribute to the Development of Brain Arteriovenous Malformations in Mice.

We have previously demonstrated that deletion of activin receptor-like kinase 1 (Alk1) or endoglin in a fraction of endothelial cells (ECs) induces brain arteriovenous malformations (bAVMs) in adult mice upon angiogenic stimulation. Here, we addressed three related questions: (1) could Alk1- mutant bone marrow (BM)-derived ECs (BMDECs) cause bAVMs? (2) is Alk1- ECs clonally expended during bAVM development? and (3) is the number of mutant ECs correlates to bAVM severity? For the first question, we transplanted BM from PdgfbiCreER;Alk12f/2f mice (EC-specific tamoxifen-inducible Cre with Alk1-floxed alleles) into wild-type mice, and then induced bAVMs by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor and intra-peritoneal injection of tamoxifen. For the second question, clonal expansion was analyzed using PdgfbiCreER;Alk12f/2f;confetti+/- mice. For the third question, we titrated tamoxifen to limit Alk1 deletion and compared the severity of bAVM in mice treated with low and high tamoxifen doses. We found that wild-type mice with PdgfbiCreER;Alk12f/2f BM developed bAVMs upon VEGF stimulation and Alk1 gene deletion in BMDECs. We also observed clusters of ECs expressing the same confetti color within bAVMs and significant proliferation of Alk1- ECs at early stage of bAVM development, suggesting that Alk1- ECs clonally expanded by local proliferation. Tamoxifen dose titration revealed a direct correlation between the number of Alk1- ECs and the burden of dysplastic vessels in bAVMs. These results provide novel insights for the understanding of the mechanism by which a small fraction of Alk1 or endoglin mutant ECs contribute to development of bAVMs.

Propionibacterium acnes-Derived Circulating Immune Complexes in Sarcoidosis Patients

Propionibacterium acnes is a potential etiologic agent of sarcoidosis and a dysregulated immune response to the commensal bacterium is suspected to cause granuloma formation. P. acnes-derived insoluble immune complexes were recently demonstrated in sinus macrophages of sarcoidosis lymph nodes, suggesting local proliferation of the bacterium in affected organs. In the present study, we developed a method for detecting P. acnes-derived immune complexes in human blood by measuring the concentration of P. acnes-specific lipoteichoic acid (PLTA) detectable after an antigen retrieval pretreatment of plasma samples. Before pretreatment, anti-PLTA antibody was detected and PLTA could not be detected, in all plasma samples from 51 sarcoidosis patients and 35 healthy volunteers. After pretreatment, however, a significant level of PLTA (>105 ng/mL) was detected in 33 (65%) sarcoidosis patients and 5 (14%) control subjects, with 86% specificity and 65% sensitivity for sarcoidosis. In both groups, plasma anti-PLTA antibody titers did not differ between samples with and without detection of PLTA. PLTA levels were abnormally increased (>202 ng/mL) in 21 (41%) sarcoidosis patients. These findings suggest that P. acnes-derived circulating immune complexes present in human blood are abnormally increased in many sarcoidosis patients, presumably due to local proliferation of the bacterium in the affected organs.

Pulpbow: A Method to Study the Vasculogenic Potential of Mesenchymal Stem Cells from the Dental Pulp.

Understanding how Mesenchymal Stem Cells (MSCs) form blood vessels is critical for creating mechanism-based approaches for the therapeutic use of these cells. In addition, understanding the determinants and factors involved in lineage hierarchy is fundamental to creating accurate and reliable techniques for the study of stem cells in tissue engineering and repair. Dental Pulp Stem Cells (DPSC) from permanent teeth and Stem cells from Human Exfoliated Deciduous teeth (SHED) are particularly interesting sources for tissue engineering as they are easily accessible and expandable. Previously, we have shown that DPSCs and SHEDs can differentiate into endothelial cells and form functional blood vessels through vasculogenesis. Here, we described how we created the “pulpbow” (pulp + rainbow), a multicolor tag experimental model that is stable, permanent, unique to each cell and passed through generations. We used the pulpbow to understand how dental pulp stem cells contributed to blood vessel formation in 3D models in in vitro and ex vivo live cell tracking, and in vivo transplantation assays. Simultaneous tracking of cells during sprout formation revealed that no single multicolor-tagged cell was more prone to vasculogenesis. During this process, there was intense cell motility with minimal proliferation in early time points. In later stages, when the availability of undifferentiated cells around the forming sprout decreased, there was local clonal proliferation mediated by proximity. These results unveiled that the vasculogenesis process mediated by dental pulp stem cells is dynamic and proximity to the sprouting area is critical for cell fate decisions.

Ablation of arginyl-tRNA-protein transferase in oligodendrocytes impairs central nervous system myelination.

Addition of arginine (Arg) from tRNA can cause major alterations of structure and function of protein substrates. This post-translational modification, termed protein arginylation, is mediated by the enzyme arginyl-tRNA-protein transferase 1 (Ate1). Arginylation plays essential roles in a variety of cellular processes, including cell migration, apoptosis, and cytoskeletal organization. Ate1 is associated with neuronal functions such as neurogenesis and neurite growth. However, the role of Ate1 in glial development, including oligodendrocyte (OL) differentiation and myelination processes in the central nervous system, is poorly understood. The present study revealed a peak in Ate1 protein expression during myelination process in primary cultured OLs. Post-transcriptional downregulation of Ate1 reduced the number of OL processes, and branching complexity, in vitro. We conditionally ablated Ate1 from OLs in mice using 2',3'-cyclic nucleotide 3'-phosphodiesterase-Cre promoter ("Ate1-KO" mice), to assess the role of Ate1 in OL function and axonal myelination in vivo. Immunostaining for OL differentiation markers revealed a notable reduction of mature OLs in corpus callosum of 14-day-old Ate1-KO, but no changes in spinal cord, in comparison with wild-type controls. Local proliferation of OL precursor cells was elevated in corpus callosum of 21-day-old Ate1-KO, but was unchanged in spinal cord. Five-month-old Ate1-KO displayed reductions of mature OL number and myelin thickness, with alterations of motor behaviors. Our findings, taken together, demonstrate that Ate1 helps maintain proper OL differentiation and myelination in corpus callosum in vivo, and that protein arginylation plays an essential role in developmental myelination.

An Ambiguous Clinical Presentation of a Gingival Plasma Cell Granuloma – A Case Report

Plasma cell granuloma (PCG) is a rare localized benign proliferation of polyclonal mature plasma cells. The etiopathogenesis of the PCG remains inexplicit. Although it primarily occurs in the lungs, intraoral variants, involving the gingiva, tongue, buccal mucosa, have been reported too. Here we report a case of a 19-year-old female patient with mandibular anterior gingival exophytic growth that gave an impression of pyogenic granuloma clinically. The overgrown tissue was excised and histological examination revealed inflammatory cell infiltrate containing sheets of plasma cells. This case highlights the presence of a PCG having a periodontal origin. As intraoral occurrences of PCG are uncommon, such observations should be well documented and added to the existing literature. Advanced investigations such as immunohistochemistry can be done, which rule out the possibility of any malignancy, as seen in cases of plasmacytoma that mimic PCG (no malignant potential).

Complete root specimen of plants grown in soil-filled root box: sampling, measuring, and staining method

BackgroundDetailed datasets containing root system and its architecture in soil are required to improve understanding of resource capture by roots. However, most of the root study methods have paid little attention to make and preserve whole root specimens. This study introduces root system sampling equipment that makes the entire root specimen with minimum impairment and without displacement of the spatial arrangement of the root system in root boxes. The objectives are to assess: whether the equipment can rapidly sample the entire root system; whether root surface area is measurable from a scanned digital image of the root specimen; and whether staining of the entire root specimens would provide multidimensional visual information on the interaction between soil and physiological function of root system architecture (RSA). For validation, we examined the root response of two soybean cultivars to arbuscular mycorrhizal (AM) inoculation and the effect of waterlogging stress on the physiological activity of buckwheat RSA.ResultsThe root boxes allowed soybean and buckwheat plants to grow uniformly across the replications. Both species showed significant differences between cultivars and/or among treatments in shoot and root traits. The equipment enabled to sample the whole-root specimens of soybean and buckwheat, where the tips of the fine roots were alive (diameter < 0.2 mm). Also, the whole root specimens of soybean were made in about 7 min. The root surface area calculated from the scanned soybean specimens showed a significant correlation with that calculated from the roots spread out in water (a common method). Staining of the soybean root specimens enabled us to observe the localized root proliferation induced by AM colonization. Moreover, staining of the buckwheat root specimens made it possible to examine the respiratory activity of each root at different depths.ConclusionsThe present method realized: fast and accurate production of the whole root specimen and precise calculation of the specimens’ root surface area. Moreover, staining of the root specimens enabled analyzing the interaction between soil and physiological function of RSA. The evaluation of root traits, using our methods, will contribute to developing agronomic management and breeding program for sustainable food production.

Self-renewal of peripheral nerve resident macrophage: does it represent a unique activation status?

Self-renewal of peripheral nerve resident macrophage: does it represent a unique activation status?

Increased Monocyte-Derived CD11b+ Macrophage Subpopulations Following Cigarette Smoke Exposure Are Associated With Impaired Bleomycin-Induced Tissue Remodelling.

RationaleThe accumulation of macrophages in the airways and the pulmonary interstitium is a hallmark of cigarette smoke-associated inflammation. Notably, pulmonary macrophages are not a homogenous population but consist of several subpopulations. To date, the manner in which cigarette smoke exposure affects the relative composition and functional capacity of macrophage subpopulations has not been elucidated.MethodsUsing a whole-body cigarette smoke exposure system, we investigated the impact of cigarette smoke on macrophage subpopulations in C57BL/6 mice using flow cytometry-based approaches. Moreover, we used bromodeoxyuridine labelling plus Il1a-/- and Il1r1-/- mice to assess the relative contribution of local proliferation and monocyte recruitment to macrophage accumulation. To assess the functional consequences of altered macrophage subpopulations, we used a model of concurrent bleomycin-induced lung injury and cigarette smoke exposure to examine tissue remodelling processes.Main ResultsCigarette smoke exposure altered the composition of pulmonary macrophages increasing CD11b+ subpopulations including monocyte-derived alveolar macrophages (Mo-AM) as well as interstitial macrophages (IM)1, -2 and -3. The increase in CD11b+ subpopulations was observed at multiple cigarette smoke exposure timepoints. Bromodeoxyuridine labelling and studies in Il1a-/- mice demonstrated that increased Mo-AM and IM3 turnover in the lungs of cigarette smoke-exposed mice was IL-1α dependent. Compositional changes in macrophage subpopulations were associated with impaired induction of fibrogenesis including decreased α-smooth muscle actin positive cells following intratracheal bleomycin treatment. Mechanistically, in vivo and ex vivo assays demonstrated predominant macrophage M1 polarisation and reduced matrix metallopeptidase 9 activity in cigarette smoke-exposed mice.ConclusionCigarette smoke exposure modified the composition of pulmonary macrophage by expanding CD11b+ subpopulations. These compositional changes were associated with attenuated fibrogenesis, as well as predominant M1 polarisation and decreased fibrotic activity. Overall, these data suggest that cigarette smoke exposure altered the composition of pulmonary macrophage subpopulations contributing to impaired tissue remodelling.

Spontaneous regression of a rectal tonsil presenting as a large submucosal tumor

Rectal tonsils are localized hyperplastic lymphoid tissues in the rectum, and the initial endoscopic findings are consistent with those for neoplastic lesions. However, rectal tonsils are benign entities, and the diagnosis should be made cautiously. A 70‐year‐old man presented with pain on defecation with rectal bleeding. Colonoscopy revealed a 3‐cm protruding mass in the rectum with mucosal erosion, but no malignant features were observed on forceps biopsy. Endoscopic ultrasonography (EUS) showed that the lesion was a hypoechoic mass without blood flow. Fine needle aspiration under EUS revealed no malignant components, although the size of the lesion had shrunk, and symptoms, such as blood‐stained stool, tenesmus, and discomfort during defecation, had resolved. A second forceps biopsy showed intermediate‐sized lymphocytes without lymphoepithelial lesions. Based on immunostaining, the lesion was diagnosed as a rectal tonsil.Rectal tonsils occur due to localized proliferation of reactive lymphoid follicles in the submucosa or muscularis mucosa. However, endoscopic diagnosis is difficult since less invasive treatment is performed for neoplastic lesions of the rectum to preserve the function of the anal sphincter. Diagnosis and treatment of small lesions might be possible by endoscopic resection; however, for relatively large lesions, formulating a diagnosis based only on biopsy specimens becomes even more difficult. Therefore, repeated biopsies might be helpful for the diagnosis of rectal tonsils and for excluding other neoplasms.

MM-338: Factors of an Unfavorable Prognosis in Patients with Solitary Plasmacytoma Among Residents of the Gomel Region of Belarus

Introduction Solitary plasmacytoma is a tumor of plasma cells with local proliferation without signs of systemic damage and a high risk of progression to MM. Depending on the presence of a lesion in the bone or soft tissues, there are solitary plasmacytoma of bone and solitary extramedullary plasmacytoma. There are currently few data available on prognostic factors. Methods The study included 24 patients (4 SEP patients, 20 SBP patients) of the Gomel region (Belarus) 2018–2021 with different anatomical localization. The diagnosis was histologically confirmed. The average age was 62 (from 41 to 79 years); female patients prevailed 54.2% (13/11). All patients underwent aspiration biopsy with IFT and FISH, trepanobiopsy with immunohistochemical examination of the BM, and X-ray examination of the skeletal bones. Results were assessed after 3 years of observation. The signs of progression include the appearance of any one of the CRAB-criteria. Results The presence of clonal PCs 5 cm) were detected in 4 patients (all progressed to MM). The progression of the disease to MM was recorded in 7 patients (29.2%). The period to progression was 10 months (media) (3–18). An immunophenotypic study in these patients revealed a significant decrease in the CD95 level (p = 0.001) and in 71.4%, a significant excess of the TNF-a level (p = 0.001) and a significant excess of the B2 microglobulin level (p = 0.001). The 3-year survival rate was 100%. Local relapse developed after 4 courses of PAD in 1 patient who progressed to MM. Conclusion The progression of the disease in patients was associated with the presence of cytogenetic changes in combination with the presence of aberrant or clonal cells in BM 5 cm).

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Physiological and Pathological Processes within the Gastrointestinal Tract: A Review.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the central nervous system (CNS) and many peripheral organs, such as the digestive tract, endocrine, reproductive and respiratory systems, where it plays different regulatory functions and exerts a cytoprotective effect. The multifarious physiological effects of PACAP are mediated through binding to different G protein-coupled receptors, including PAC1 (PAC1-R), VPAC1 (VPAC1-R) and VPAC2 (VPAC2-R) receptors. In the gastrointestinal (GI) tract, PACAP plays an important regulatory function. PACAP stimulates the secretion of digestive juices and hormone release, regulates smooth muscle contraction, local blood flow, cell migration and proliferation. Additionally, there are many reports confirming the involvement of PACAP in pathological processes within the GI tract, including inflammatory states, neuronal injury, diabetes, intoxication and neoplastic processes. The purpose of this review is to summarize the distribution and pleiotropic action of PACAP in the control of GI tract function and its cytoprotective effect in the course of GI tract disorders.

Implantation and repair of 3D printed myocardial patch in rabbit model of myocardial infarction

In this study, BMSCs were induced to differentiate into cardiomyocytes by 5-azacytidine, and combined with sodium alginate and gelatin to construct myocardial patch in vitro by 3D bio-printing, then it was attached to the myocardial infarction site of rabbit myocardial infarction model. Cytokines such as brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) in peripheral blood were detected by ELISA after operation. The results showed that the absolute value of cTnI in each group was more than 0.04 ng/ml after surgery, and there was no significant difference in the data at four time points in each group. As time went by, cTn-I did not decrease. BNP in both the control group and the experimental group was significantly higher than the blank group. However, BNP in the experimental group fell after the 2 nd week, but it was still higher than that in the blank group. Histological examination showed that there was no cardiomyocyte formation around the patch, only fibrous tissue and many small blood vessels and microvessels were found. And the patch could decrease the collagen fibers to some extent. These results suggested that the myocardial patch did not repair the injured myocardial cells by forming new myocardial cells in the myocardial infarction site of animals, but it could promote the local vascular proliferation, improve the blood supply to the myocardial infarction site, decrease the collagen fibers and thus improve the cardiac function.

Neuropathological effects of chronically implanted, intracortical microelectrodes in a tetraplegic patient

Objective. Intracortical microelectrode arrays (MEA) can be used as part of a brain–machine interface system to provide sensory feedback control of an artificial limb to assist persons with tetraplegia. Variability in functionality of electrodes has been reported but few studies in humans have examined the impact of chronic brain tissue responses revealed postmortem on electrode performance in vivo. Approach. In a tetraplegic man, recording MEAs were implanted into the anterior intraparietal area and Brodmann’s area 5 (BA5) of the posterior parietal cortex and a recording and stimulation array was implanted in BA1 of the primary somatosensory cortex (S1). The participant expired from unrelated causes seven months after MEA implantation. The underlying tissue of two of the three devices was processed for histology and electrophysiological recordings were assessed. Main results. Recordings of neuronal activity were obtained from all three MEAs despite meningeal encapsulation. However, the S1 array had a greater encapsulation, yielded lower signal quality than the other arrays and failed to elicit somatosensory percepts with electrical stimulation. Histological examination of tissues underlying S1 and BA5 implant sites revealed localized leptomeningeal proliferation and fibrosis, lymphocytic infiltrates, astrogliosis, and foreign body reaction around the electrodes. The BA5 recording site showed focal cerebral microhemorrhages and leptomeningeal vascular ectasia. The S1 site showed focal tissue damage including vascular recanalization, neuronal loss, and extensive subcortical white matter necrosis. The tissue response at the S1 site included hemorrhagic-induced injury suggesting a likely mechanism for reduced function of the S1 implant. Significance. Our findings are similar to those from animal studies with chronic intracortical implants and suggest that vascular disruption and microhemorrhage during device implantation are important contributors to overall array and individual electrode performance and should be a topic for future device development to mitigate tissue responses. Neurosurgical considerations are also discussed.

Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners.

Kupffer cells (KCs), which are liver-resident macrophages, originate from the fetal yolk sac and represent one of the largest macrophage populations in the body. However, the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial. Here, we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy (PHx) and uncover the underlying mechanisms. By using several strains of genetically modified mice and performing immunohistochemical analyses, we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx. Peak KC proliferation was impaired in Il6-knockout (KO) mice and restored after the administration of IL-6 protein, whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice. The source of IL-6 was identified using hepatocyte- and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx. Moreover, peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx, suggesting that IL-6 signaling directly promotes KC proliferation. Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1 (SIRT1) contributed to IL-6-mediated KC proliferation in vitro. Genetic deletion of the Sirt1 gene in myeloid cells, including KCs, impaired KC proliferation after PHx. In conclusion, our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation, which is dependent on IL-6 and SIRT1 activation in KCs.