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Simple Summary: Therapeutic options for GEP-NETs are very limited, and at the same time, the incidence of these cancers is increasing. The evidence has shown that multiple neoplasms can be successfully treated with immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors. Crucial to determining a patient's response to immunotherapy is access to the tumor microenvironment. Currently, there is no consistency regarding the future role of TME and immunotherapy in GEP-NETs. Thus, this review points to the solution in selecting a concrete patient group that, based on tumor features can benefit from immunotherapy. Neuroendocrine neoplasms (NENs) are a heterogenous and recurrent group of malignancies originating from neuroendocrine secretory cells diffused on all parts of the human body. Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) account for most NENs. Considering the abundance of possible origins, locations, and tumor specifications, there is still no consensus about optimal treatment options for these neoplasms. In light of the escalating immunotherapeutic approaches, it is crucial to define indications for such therapy in GEP-NETs. Bearing in mind the significance of pathophysiological mechanisms and tumor microenvironment (TME) impact on carcinogenesis, defining TME structure and correlation with the immune system in GEP-NETs appears essential. This paper aimed to assess the characterization of the tumor immune microenvironment for a better understanding of the possible therapeutic options in GEP-NETS. The authors performed a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 3800 articles identified through database searching, 292 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis. This paper sums up the research on the immune cell infiltrates, immune checkpoint expression, cytokine profile, neoangiogenesis, and microbiome in the TME of GEP-NETs. [ABSTRACT FROM AUTHOR]

Cystectomy is the removal of all or part of the urinary bladder. It has been observed that there is significant regrowth of the bladder after partial cystectomy and this has been proposed to be through regeneration of the organ. Regrowth of tissue in mammals has been proposed to involve compensatory mechanisms that share many characteristics of true regeneration, like the growth of specialized structures such as blood vessels or nerves. However, the overall structure of the normal organ is not achieved. Here we tested if bladder growth after subtotal cystectomy (STC, removal of 50% of the bladder) was compensatory or regenerative. To do this we subjected adult female mouse bladders to STC and assessed regrowth using several established cellular parameters including histological, gene expression, cytokine accumulation and cell proliferation studies. Bladder function was analyzed using cystometry and the voiding stain on paper (VSOP) technique. We found that STC bladders were able to increase their ability to hold urine with the majority of volume restoration occurring within the first two weeks. Regenerating bladders had thinner walls with less mean muscle thickness, and they showed increased collagen deposition at the incision as well as throughout the bladder wall suggesting that fibrosis was occurring. Cell populations differed in their response to injury with urothelial regeneration complete by day 7, but stromal and detrusor muscle still incomplete after 8wks. Cells incorporated EdU when administered at the time of surgery and tracing of EdU positive cells over time indicated that many newborn cells originate at the incision and move mediolaterally. Basal urothelial cells and bladder mesenchymal stem cells but not smooth muscle cells significantly incorporated EdU after STC. Since anti-inflammatory cytokines play a role in regeneration, we analyzed expressed cytokines and found that no anti-inflammatory cytokines were present in the bladder 1wk after STC. Our findings suggest that bladder regrowth after cystectomy is compensatory and functions to increase the volume that the bladder can hold. This finding sets the stage for understanding how the bladder responds to cystectomy and how this can be improved in patients after suffering bladder injury. [ABSTRACT FROM AUTHOR]

Due to its strong proliferation-reducing effects on keratinocytes, and also anti-inflammatory properties, the isoflavone genistein has already been proposed as a possible antipsoriatic compound. As there is still no detailed information on this topic, we examined the effects of genistein by using an in vitro model of both, normal and “psoriasis-like” keratinocytes at this stage of our work exhaustively testing the selected flavonoid in a mono-treated experimental design. Gene expression studies revealed transcriptional changes that confirms known disease-associated pathways and highlights many psoriasis-related genes. Our results suggested that aberrant expression of genes contributing to the progress of psoriasis could be improved by the action of genistein. Genistein prevented “cytokine mix” as well as TNF-α-induced NF-κB nuclear translocation, with no effect on the PI3K signaling cascade, indicating the luck of turning this pathway into NF-κB activation. It could have attenuated TNF-α and LPS-induced inflammatory responses by suppressing ROS activation. Regardless of the type of keratinocyte stimulation used, reduction of cytokine IL-8, IL-20 and CCL2 production (both at RNA and protein level) following genistein treatment was visible. Because investigations of other groups supported our commentary on potential administration of genistein as a potential weapon in the armamentarium against psoriasis, it is believed that this paper should serve to encourage researchers to conduct further studies on this subject. [ABSTRACT FROM AUTHOR]

Primary dysmenorrhea is one of the most common gynecological complaints in young women, but potential peripheral immunologic features underlying this condition remain undefined. In this paper, we compared 84 common cytokine gene expression profiles of peripheral blood mononuclear cells (PBMCs) from six primary dysmenorrheic young women and three unaffected controls on the seventh day before (secretory phase), and the first (menstrual phase) and the fifth (regenerative phase) days of menstruation, using a real-time PCR array assay combined with pattern recognition and gene function annotation methods. Comparisons between dysmenorrhea and normal control groups identified 11 (nine increased and two decreased), 14 (five increased and nine decreased), and 15 (seven increased and eight decreased) genes with ≥2-fold difference in expression (P<0.05) in the three phases of menstruation, respectively. In the menstrual phase, genes encoding pro-inflammatory cytokines (IL1B, TNF, IL6, and IL8) were up-regulated, and genes encoding TGF-β superfamily members (BMP4, BMP6, GDF5, GDF11, LEFTY2, NODAL, and MSTN) were down-regulated. Functional annotation revealed an excessive inflammatory response and insufficient TGF-β superfamily member signals with anti-inflammatory consequences, which may directly contribute to menstrual pain. In the secretory and regenerative phases, increased expression of pro-inflammatory cytokines and decreased expression of growth factors were also observed. These factors may be involved in the regulation of decidualization, endometrium breakdown and repair, and indirectly exacerbate primary dysmenorrhea. This first study of cytokine gene expression profiles in PBMCs from young primary dysmenorrheic women demonstrates a shift in the balance between expression patterns of pro-inflammatory cytokines and TGF-β superfamily members across the whole menstrual cycle, underlying the peripheral immunologic features of primary dysmenorrhea. [ABSTRACT FROM AUTHOR]

Aucklandia costus Falc. a medicinal plant is native to the Himalayan region and synonymous with Saussurea costus, Saussurea lappa, and Aucklandia lappa. It has an ancient background of being used ethnopharmacologically for various body ailments. According to Ayurveda, Unani, Siddha, and Traditional Chinese Medicine, Costus roots are recommended for leukoderma, liver, kidney, blood disorders, Qi stagnation, and tridosha. Root and powder are used orally with warm water to cure gastric problems, and the paste is applied to the inflamed area to relieve pain. Root paste is applied on the skin to cure boils, blisters, and leprosy. The aim of the present review is to establish a correlation among the ethnopharmacological uses and scientific studies conducted on A. costus with chemical constituents, safety & toxicity data including future directions for its conservation with higher yield and effect. The study was conducted by studying books, research papers, and literature in history, agroforestry, phytopharmacology of Himalayan plants using international databases, publication, Red data book, and reports. The search engines: Pubmed, Scopus, Wiley Inter-science, Indian Materia Medica, Science Direct, and referred journals are referenced. The literature collected from databases, journals, websites, and books mentioned the use of costus roots in local and traditional practices. CITES included A. costus in a critically endangered category due to lack of cultural practices and overexploitation from wild. A. costus roots are known since 13th century for use in ancient Ayurvedic products but the scientific evaluation is of future research interest. A correlation of traditional uses with scientific studies has been explored to assess the effect of root powder, extract, oil and isolated constituents: Costunolids, Saussureamine B and Dehydrocostus lactone etc. in gastric ulceration and lesions; inhibition of antigen-induced degranulation, mucin production, number of immune cells, eosinophils, and expression and secretion of Th2 cytokines (IL-4 and IL-13) in asthma. The inhibition of pro-inflammatory mediators is also reported by Cynaropicrin, Alantolactone, Caryophyllene, Costic acid. Also, the sesquiterpene lactones has profound effect in inhibition of inflammatory stages and induced apoptotic cascades in cancer. Very few data on the safety and toxicity of plant parts have been noted which needs to be evaluated scientifically. A. costus have been noted to have remarkable effect for gastric, hepatic, inflammatory, respiratory, cancer, skin problems but there were several errors in selection of plant material, authentification, selection of dose, assessment, selection of standard and control have been identified. Therefore, a schematic drug development and research strategy exploiting the potential of plant extract, fraction, products and probable constituents, costunolide, dehydrocostus lactone, cynaropicrin, saussureamine assuring dose-response relationship and safety may be determined under pre-clinical which may be extrapolated to clinical level. An evaluation of phytochemicals in A. costus collected from different geographical location in Himalayas may be drawn to identify and conserve the higher yielding plant. Image 1 [ABSTRACT FROM AUTHOR]