The skin is a complex organ consisting of the epidermis, dermis, and skin appendages, including the hair follicle and sebaceous gland. Wound healing in adult mammals results in scar formation without any skin appendages. Studies have reported remarkable examples of scarless healing in fetal skin and appendage regeneration in adult skin following the infliction of large wounds. The models used in these studies have offered a new platform for investigations of the cellular and molecular mechanisms underlying wound healing and skin regeneration in mammals. In this article, we will focus on the contribution of skin appendages to wound healing and, conversely, skin appendage regeneration following injuries.
Background : Allergic rhinitis (AR) is strongly associated with a type 2 response, characterized by the cytokines IL-5, IL-4 and IL-13. Several studies have implicated ILC2 and TH2A (CD161+ TH2) but it is not yet entirely clear which subsets are driving the common allergic reactions underlying AR. The objective of this study aims to identify critical pathogenic cell populations associated with AR and to determine their phenotype and functional contribution to disease progression. Methods : We identified integral allergic-specific cell types by transcriptomic sequencing. Whole blood, PBMCs and plasma from a cross-sectional cohort of 216 individuals were analysed by 9-colour flow cytometry and ultra-sensitive cytokine bead arrays using unsupervised clustering algorithms. Clinically active AR cases were further analysed by functional mass cytometry to define phenotype and cytokine secretion (IL-2, IL-3, IL-4, IL-5, IL-9, IL13, IL-17A and IL-22) as well as the expression of the hematopoietic prostaglandin D synthetase (HPGDS). Results : The unbiased analysis revealed that atopy and AR manifestation corelated only with eosinophils, plasma IL-5 and CD161+ TH2 cells. In-depth characterization further revealed that the CD45RB CD161+ TH2 subset were most closely associated with severity. This subset is able to concomitantly secrete multiple cytokines including IL-5, IL-13 and IL-4 and has been previously reported to be associated with other eosinophilic allergies. Conclusion : CD45RB CD161+ TH2 have key roles in driving the allergic response in AR. Neutralizing the CD45RB CD161+ TH2 subset should disrupt the allergic response pathway, thus providing a target for lasting therapeutic interventions.
Emerging treatments for advanced PCa continue to target androgen signalling leading to prolonged androgen deprivation. This induces metabolic dysfunction and hyperinsulinaemia which is specifically associated with more rapid progression to CRPC, but is not clinically addressed. The aims of our research is to understand the mechanisms by which insulin contributes to cancer progression and how these pathways are affected by insulin‐lowering therapies such as metformin. Transcriptomic analyses identified that insulin upregulated cell survival and invasion pathways and modulated metabolic pathways. Insulin upregulated Bcl2 and Bcl‐XL and down‐regulated pro‐apoptotic genes Bim and. Androgen deprivation was associated with a 15% reduction in spare respiratory capacity which was restored with 10 nM DHT, or with 10 nM insulin and correlated to resistance to doxyrubicin‐induced apoptosis, measured via Caspase 3 cleavage. We have observed that metformin counteracts insulin‐driven survival pathways, reduces oxidative capacity in androgen‐deprived PCa cells and sensitises cells to apoptosis. These results provide rationale for the combined therapeutic use of insulin‐lowering therapies with ADT.
The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.
492 Background: Though disparate outcomes in colon cancer may be multifactorial, racial/ethnic disparities persist despite adjusting for these factors. Genetic alterations, including single-nucleotide polymorphisms (SNPs), have been shown to predict treatment response in colorectal cancer. Here, we evaluate the variability of genetic alterations in colon cancer patients by examining SNPs in major racial/ethnic groups. Methods: We obtained 76 normal tissue specimens from colon cancer patients of different race/ethnicity at our institution. DNA was extracted and analyzed for 6 SNPs (MTHFR 677C>T, XRCC1 685C>T, XRCC1 1301G>A, XPD 2282A>C, TP53 215G>C, and CCND1 870G>A) by polymerase chain reaction and direct sequencing. Prevalence of each allelic combination was compared between groups by the chi-square test. Results: Archived colon cancer tissues were obtained from whites, blacks, Hispanics and Asians (n=19 per group). From genotyping, we identified statistically significant differences in prevalence of CCND1 870G>A between groups ( Table , p=0.0428). Specifically, whites and Asians had significantly higher prevalence of CCND1 870G>A than blacks and Hispanics (100% and 94%, vs. 68% and 79%, respectively). Furthermore, whites and Asians were more frequently heterozygous (G/A) for the SNP (89% in both), whereas Hispanics comprised the largest proportion (16%) of patients homozygous for CCND1 870G>A. Overall, the allelic frequency of CCND1 870G>A varied among the racial/ethnic groups. Other SNPs in treatment-related pathways were evaluated, but there was no difference in prevalence of the other 5 SNPs between groups. Conclusions: Our findings demonstrate that detection of specific genetic polymorphisms differs between the major racial/ethnic groups with colon cancer. Differences in the prevalence of CCND1 870G>A, which affects cell-cycle progression, suggests a potential mechanism for disparities in cancer susceptibility and progression. Therefore, identification of such genetic variability may support a genetic basis for racial disparities in cancer outcomes. [Table: see text]
We investigated whether a 28-day course of potent antiretroviral therapy, initiated at a time point (48 h postinoculation) following simian immunodeficiency virus (SIV) inoculation when the acquisition of a viral infection was virtually assured, would sufficiently sensitize the immune system and result in controlled virus replication when treatment was stopped. The administration of tenofovir 48 h after SIV inoculation to six Mamu-A*01-negative rhesus macaques did, in fact, potently suppress virus replication in all of the treated rhesus macaques, but plasma viral RNA rapidly became detectable in all six animals following its cessation. Unexpectedly, the viral set points in the treated monkeys became established at two distinct levels. Three controller macaques had chronic phase virus loads in the range of 1 x 10(3) RNA copies/ml, whereas three noncontroller animals had set points of 2 x 10(5) to 8 x 10(5) RNA copies/ml. All of the noncontroller monkeys died with symptoms of immunodeficiency by week 60 postinfection, whereas two of the three controller animals were alive at week 80. Interestingly, the three controller macaques each carried major histocompatibility complex class I alleles that previously were reported to confer protection against SIV, and two of these animals generated cytotoxic T-lymphocyte escape viral variants during the course of their infections.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
'/%3e%3c/defs%3e%3cpath fill='%23012169' d='M0 0h10080v5040H0z'/%3e%3cpath stroke='%23fff' stroke-width='.6' d='m0 0 6 3m0-3L0 3' clip-path='url(%23b)' transform='scale(840)'/%3e%3cpath stroke='%23e4002b' stroke-width='.4' d='m0 0 6 3m0-3L0 3' clip-path='url(%23c)' transform='scale(840)'/%3e%3cpath stroke='%23fff' stroke-width='840' d='M2520 0v2520M0 1260h5040'/%3e%3cpath stroke='%23e4002b' stroke-width='504' d='M2520 0v2520M0 1260h5040'/%3e%3cg fill='%23fff'%3e%3cuse xlink:href='%23d' x='2520' y='3780'/%3e%3cuse xlink:href='%23a' x='7560' y='4200'/%3e%3cuse xlink:href='%23a' x='6300' y='2205'/%3e%3cuse xlink:href='%23a' x='7560' y='840'/%3e%3cuse xlink:href='%23a' x='8680' y='1869'/%3e%3cuse xlink:href='%23e' x='8064' y='2730'/%3e%3c/g%3e%3c/svg%3e)