Normal stem cells in cancer prone epithelial tissues

The concept of a cancer stem cell is not a new one, being first suggested over 100 years ago. Over recent years the concept has enjoyed renewed enthusiasm, partly because of our growing understanding of the nature of somatic stem cells, but also because of a growing realisation that the development of strategies that target cancer stem cells may offer considerable advantages over conventional approaches. However, despite this renewed enthusiasm the existence of cancer stem cells remains controversial in many tumour types and any potential relationship to the normal stem cell pool remains poorly defined. This review summarises key elements of our understanding of the normal stem cell populations within animal models of the predominant cancer prone epithelial tissues, and further investigates the potential links between these populations and putative cancer stem cells

Auditory Feedback Control of Vocal Pitch during Sustained Vocalization: A Cross-Sectional Study of Adult Aging

Background: Auditory feedback has been demonstrated to play an important role in the control of voice fundamental frequency (F0), but the mechanisms underlying the processing of auditory feedback remain poorly understood. It has been well documented that young adults can use auditory feedback to stabilize their voice F0 by making compensatory responses to perturbations they hear in their vocal pitch feedback. However, little is known about the effects of aging on the processing of audio-vocal feedback during vocalization. Methodology/Principal Findings: In the present study, we recruited adults who were between 19 and 75 years of age and divided them into five age groups. Using a pitch-shift paradigm, the pitch of their vocal feedback was unexpectedly shifted 650 or 6100 cents during sustained vocalization of the vowel sound/u/. Compensatory vocal F0 response magnitudes and latencies to pitch feedback perturbations were examined. A significant effect of age was found such that response magnitudes increased with increasing age until maximal values were reached for adults 51–60 years of age and then decreased for adults 61–75 years of age. Adults 51–60 years of age were also more sensitive to the direction and magnitude of the pitch feedback perturbations compared to younger adults. Conclusion: These findings demonstrate that the pitch-shift reflex systematically changes across the adult lifespan. Understanding aging-related changes to the role of auditory feedback is critically important for our theoretica

Blood Glucose Levels Regulate Pancreatic β-Cell Proliferation during Experimentally-Induced and Spontaneous Autoimmune Diabetes in Mice

Type 1 diabetes mellitus is caused by immune-mediated destruction of pancreatic beta-cells leading to insulin deficiency, impaired intermediary metabolism, and elevated blood glucose concentrations. While at autoimmune diabetes onset a limited number of beta-cells persist, the cells' regenerative potential and its regulation have remained largely unexplored. Using two mouse autoimmune diabetes models, this study examined the proliferation of pancreatic islet ss-cells and other endocrine and non-endocrine subsets, and the factors regulating that proliferation.We adapted multi-parameter flow cytometry techniques (including DNA-content measurements and 5'-bromo-2'-deoxyuridine [BrdU] incorporation) to study pancreatic islet single cell suspensions. These studies demonstrate that beta-cell proliferation rapidly increases at diabetes onset, and that this proliferation is closely correlated with the diabetic animals' elevated blood glucose levels. For instance, we show that when normoglycemia is restored by exogenous insulin or islet transplantation, the beta-cell proliferation rate returns towards low levels found in control animals, yet surges when hyperglycemia recurs. In contrast, other-than-ss endocrine islet cells did not exhibit the same glucose-dependent proliferative responses. Rather, disease-associated alterations of BrdU-incorporation rates of delta-cells (minor decrease), and non-endocrine islet cells (slight increase) were not affected by blood glucose levels, or were inversely related to glycemia control after diabetes onset (alpha-cells).We conclude that murine beta-cells' ability to proliferate in response to metabolic need (i.e. rising blood glucose concentrations) is remarkably well preserved during severe, chronic beta-cell autoimmunity. These data suggest that timely control of the destructive immune response after disease manifestation could allow spontaneous regeneration of sufficient beta-cell mass to restore normal glucose homeostasis

Inorganic arsenic sorption by drinking-water treatment residual-amended sandy soil: effect of soil solution chemistry

Previous studies in our laboratory have demonstrated that drinking-water treatment residuals are effective sorbents of arsenic V. However, the effect of soil solution chemistry on arsenic V sorption by drinking-water treatment residuals-amended soils remains to be explored. The current study uses a batch incubation experimental set up to evaluate the effect of soil solution pH, competing ligands, and complexing metal on arsenic V sorption by a sandy soil (Immokalee series) amended with two rates (25 and 50 g kg-1) of aluminum and iron-based drinking-water treatment residuals. Experiments were conducted at three initial arsenic loads (125, 1,875, 3,750 mg kg-1) and a constant solid: solution ratio of 200 g L-1. An optimum equilibration time of 8 days, obtained from kinetic studies, was utilized for sorption experiments with both aluminum and iron drinking-water treatment residual-amended soil. Presence of phosphate decreased arsenic V sorption by both aluminum and iron drinking-water treatment residual amended soils, with a strong dependence on pH, drinking-water treatment residual types, drinking-water treatment residual application rates, and phosphate concentrations. Addition of sulfate had no effect on arsenic V sorption by aluminum or iron drinking-water treatment residual-amended soil. A complementing effect of calcium on arsenic V sorption was observed at higher pH. Results elucidating the effect of soil solution chemistry on the arsenic V sorption will be helpful in calibrating drinking-water treatment residual as a sorbent for remediation of arsenic-contaminated soils

Gene-expression profiles in hereditary breast cancer

Background: Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles. Methods: RNA from samples of primary tumors from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype. Results: Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations. Conclusions: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cance

Efficacy of tyrosine kinase inhibitors in Ph-like acute lymphoblastic leukemia harboring ABL-class rearrangements

Philadelphia(Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of B-precursor ALL characterized by a gene expression profile (GEP) similar to Ph-positive ALL but lacking the specific BCR-ABL1 fusion gene.1,2 Several pediatric and adult groups have reported on the poor baseline features of Ph-like ALL including a high white blood cells count (WBC) at diagnosis and a frequent association with IKZF1 intragenic deletion. Patients with Ph-like ALL are at higher risk of induction failure or high post-induction minimal residual disease (MRD) levels.3\u20135 This poor early response translates into inferior outcome in terms of event-free survival (EFS) and overall survival (OS) as compared to other B-ALL patients. Ph-like ALL was recognized as a provisional entity by the 2016 WHO classification but strict and unequivocal diagnostic criteria have not been established yet.6 Ph-like ALL are characterized by a multitude of oncogenic events that lead to the aberrant activation of cytokine receptors or signaling factors, the most frequent beeing rearrangements of CRLF2, fusions and mutations of JAK kinases and fusions involving ABL-class kinases (ABL1, ABL2, CSF1R or PDGFRB).7 As expected, Ph-like cells harboring ABL-class rearrangements have shown sensitivity to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib in vitro or in patient-derived xenograft (PDX).8\u201310 In addition, we and others have reported single experiences of clinical benefit of TKI treatment in early resistant patients.11,12 In an attempt to enable targeted therapy in B-ALL patients with poor response to chemotherapy, we have developped an integrative diagnostic strategy to identify Ph-like alterations in newly diagnosed or relapsing patients in a timely manner. Here, we report on the characteristics, response and outcome of 24 patients with B-ALL harboring ABL-class fusions who could be treated with a combination of TKI and chemotherapy, either during frontline treatment (N=19) or at relapse (N=5). Patients were initially enrolled in or treated according to pediatric FRALLE/CAALL/EORTC (NCT02716233; NCT01185886) or adult GRAALL/EWALL trials (NCT00327678; NCT02617004) in french clinical centers. Cytogenetic analyses were performed locally according to standard recommendations. Molecular analyses were performed centrally and evolved over time with the introduction of new techniques, up to the current algorithm shown in Supplementary Figure 1. Briefly, fusion transcripts are searched for using an in-house multiplexed method (derived from 13) and cases negative for classifying alterations are subjected to RNA-sequencing for detection of alternative fusions. Of the 24 patients reported here, 12 had fusions involving ABL1, including NUP214-ABL1 (n=6), ETV6-ABL1 (n=3) and other partners in single cases (RCSD1, RANBP2 and LSM14A) (Figure 1A). Nine cases had a PDGFRB rearrangement, including EBF1-PDGFRB (n=6) and other partners in single cases (NUMA1, ETV6 and ATF7IP). ZC3HAV1-ABL2 and MEF2D-CSF1R fusions were identified in single cases, and a patient with a ZMYM2-FGFR1 fusion (not strictly ABL-class) was also included in the present cohort. The resulting cohort (Table 1) included 16 males and 8 females and median age at diagnosis was 24 years (range 5-72). Two patients were previously reported (#1,24).11,14 As expected, patients had baseline characteristics and early response to treatment associated with a poor prognosis. Median WBC was 30x109/L (range 4-570x109/L). Intragenic IKZF1 deletions were detected in 11 out of 24 patients (46%). A poor response to prednisone prephase ( 651 G/L blasts in peripheral blood at day 8) was observed in 14 out of 22 evaluable patients (64%). After induction therapy, only 16 out of 24 (67%) of patients reached complete remission, all with detectable minimal residual disease (MRD), including 7 with MRD 6510-2, and only one with MRD <10-4 (Table 1, Figure 1B). In 19 patients, the ABL-class fusion was identified at initial diagnosis work-up and TKI was introduced during frontline treatment, within the first month of consolidation or salvage for most of them (n=14). In 5 patients, the Ph-like status was diagnosed at relapse and TKI was introduced in association with salvage therapy. In this retrospective study, the choice of TKI, TKI dosage, and combination was up to the physician choice. Fourteen patients were exposed to imatinib, 9 to dasatinib, one to ponatinib. Three patients were switched from imatinib to dasatinib during frontline treatment (Table 1). Among the 19 patients treated with TKI frontline, 7 out of 8 primary refractory patients subsequently achieved CR, one after a switch to dasatinib (#10). One patient died early of sepsis in a context of uncontrolled disease (#16). One patient was lost of sight after salvage until she relapsed (#13). In 14 out of 18 patients (78%), a MRD level below 10-4 was achieved within a median time of 2.5 months (range 1.4-14.8) (Figure 1B). Allogeneic hematopoietic stem cell transplant (HSCT) was performed in 9 patients, of whom 3 with a sibling donor (SIB), 4 with a matched unrelated donor (MUD), and 2 with a haploidentical donor (Haplo). All patients were in CR before HSCT and 6/9 (67%) had undetectable MRD. One patient was additionally exposed to blinatumomab in combination to dasatinib in bridge to HSCT. After a median follow-up of 36 months (range 8-73), 12 patients were alive in first CR. Six patients relapsed, 3 patients received an alternative TKI, including one in association to inotuzumab. The median remission duration and OS were not reached. At 3 years, EFS was 55% (95%CI: 27-76) and OS was 77% (95%CI: 50-91) (Figure 1C-D). The 5 patients who were treated with TKI at relapse achieved CR, including two patients who had refractory disease to several lines of treatment (#22,24). A MRD level below 10-4 was achieved in 3 patients of whom two could proceed to HSCT (1 Haplo, 1 MUD) and remained alive in remission. The three other patients further relapsed and died of progressive disease after exposition to second-line TKIs (dasatinib, n=2; ponatinib, n=1). The efficacy of TKIs in Ph-like ALL has been suggested by several case reports.11,12,15\u201317 In a large pediatric and adult cohort, Roberts et al. mentioned 11 patients with Ph-like ALL and slow response or failure to induction who achieved rapid responses upon TKI or ruxolitinib therapy.3 In frontline patients, the 3-year OS of 77% we observe compares favorably with retrospective survival rates of Ph-like adult patients treated without TKI. In the GMALL group experience in 19 adult patients with Ph-like ALL and a median age of 31 years old (range 16-59), the 5-year OS was 22%.19 In the MDACC experience, the 5-year survival of 56 Ph-like adult patients with a median age of 33.5 years (range 15-71) treated with either Hyper-CVAD or augmented BFM was 23%.7 Of note, these series included all Ph-like ALL cases characterized by GEP, and no specific subgroup analysis was performed in patients with ABL-class fusion genes. In conclusion, we report the largest cohort of patients with ABL-class kinase rearrangement exposed to TKI frontline or at relapse, and show promising MRD response and outcome similar to those observed in early trials of imatinib combined with chemotherapy in Ph-positive ALL.18 Prospective screening strategies are feasible and should be generalized to identify these high-risk patients and to propose early TKI-based intervention. In future studies, several questions remain to be adressed including the choice of TKI according to the fusion transcript, whether these patients should benefit from recently approved blinatumomab19, and finally, the benefit of HSCT in patients who achieve good MRD response upon targeted therapy