Snakes and primates have a multi-layered coevolutionary history as predators, prey, and competitors with each other. Previous work has explored the Snake Detection Theory (SDT), which focuses on the ...role of snakes as predators of primates and argues that snakes have exerted a selection pressure for the origin of primates' visual systems, a trait that sets primates apart from other mammals. However, primates also attack and kill snakes and so snakes must simultaneously avoid primates. This factor has been recently highlighted in regard to the movement of hominins into new geographic ranges potentially exerting a selection pressure leading to the evolution of spitting in cobras on three independent occasions.
Here, we provide further evidence of coevolution between primates and snakes, whereby through frequent encounters and reciprocal antagonism with large, diurnally active neurotoxic elapid snakes, Afro-Asian primates have evolved an increased resistance to α-neurotoxins, which are toxins that target the nicotinic acetylcholine receptors. In contrast, such resistance is not found in Lemuriformes in Madagascar, where venomous snakes are absent, or in Platyrrhini in the Americas, where encounters with neurotoxic elapids are unlikely since they are relatively small, fossorial, and nocturnal. Within the Afro-Asian primates, the increased resistance toward the neurotoxins was significantly amplified in the last common ancestor of chimpanzees, gorillas, and humans (clade Homininae). Comparative testing of venoms from Afro-Asian and American elapid snakes revealed an increase in α-neurotoxin resistance across Afro-Asian primates, which was likely selected against cobra venoms. Through structure-activity studies using native and mutant mimotopes of the α-1 nAChR receptor orthosteric site (loop C), we identified the specific amino acids responsible for conferring this increased level of resistance in hominine primates to the α-neurotoxins in cobra venom.
We have discovered a pattern of primate susceptibility toward α-neurotoxins that supports the theory of a reciprocal coevolutionary arms-race between venomous snakes and primates.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context:
The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown.
Objective:
To quantify the risk of thyroid cancer and ...MNG in individuals with DICER1 syndrome.
Design:
Family-based cohort study.
Setting:
National Institutes of Health (NIH) Clinical Center (CC).
Participants:
The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families.
Interventions:
Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC.
Main Outcome Measures:
The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing.
Results:
By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations.
Conclusions:
We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.
In a family-based cohort study of the DICER1 syndrome, we quantified the remarkably elevated rates of multinodular goiter and propose a model of DICER1-associated thyroid carcinogenesis.
DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of ...neoplasm incidence accounting for competing risks ("cumulative incidence") of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation.
We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors ("neoplasms," excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival.
We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers.
This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.
Context:
DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of ...multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established.
Case Description:
We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings.
Conclusions:
This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.
High-oxidation-state metal complexes with multiply bonded ligands are of great interest for both their reactivity as well as their fundamental bonding properties. This paper reports a combined ...spectroscopic and theoretical investigation into the effect of the apical multiply bonded ligand on the spin-state preferences of threefold symmetric iron(IV) complexes with tris(carbene) donor ligands. Specifically, singlet (S = 0) nitrido {PhB(ImR)3}FeN, R = tBu (1), Mes (mesityl, 2) and the related triplet (S = 1) imido complexes, {PhB(ImR)3}Fe(NR′)+, R = Mes, R′ = 1-adamantyl (3), tBu (4), were investigated by electronic absorption and Mössbauer effect spectroscopies. For comparison, two other Fe(IV) nitrido complexes, (TIMENAr)FeN+ (TIMENAr = t ris2-(3-aryl- im idazol-2-ylidene) e thylami n e; Ar = Xyl (xylyl), Mes), were investigated by 57Fe Mössbauer spectroscopy, including applied-field measurements. The paramagnetic imido complexes 3 and 4 were also studied by magnetic susceptibility measurements (for 3) and paramagnetic resonance spectroscopy: high-frequency and -field electron paramagnetic resonance (for 3 and 4) and frequency-domain Fourier-transform (FD-FT) terahertz electron paramagnetic resonance (for 3), which reveal their zero-field splitting parameters. Experimentally correlated theoretical studies comprising ligand-field theory and quantum chemical theory, the latter including both density functional theory and ab initio methods, reveal the key role played by the Fe 3d z 2 (a1) orbital in these systems: the nature of its interaction with the nitrido or imido ligand dictates the spin-state preference of the complex. The ability to tune the spin state through the energy and nature of a single orbital has general relevance to the factors controlling spin states in complexes with applicability as single molecule devices.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Ovarian sex cord-stromal tumors (OSCST) include juvenile granulosa cell tumors (JGCT), Sertoli-Leydig cell tumor (SLCT) and gynandroblastoma (GAB) among others. These ovarian sex cord-stromal tumors ...as well as other tumors including pleuropulmonary blastoma (PPB) may be associated with DICER1 mutations. We sought to describe the clinical and genetic findings from the first 107 individuals enrolled in the International Ovarian and Testicular Stromal Tumor Registry.
Medical and family history were obtained for individuals consecutively enrolled in the International Ovarian and Testicular Stromal Tumor Registry. Pathology was centrally reviewed. DICER1 sequencing was performed on blood and tumor tissue.
Of the 107 participants, 49 had SLCT, 25 had JGCT and 5 had GAB. Nearly all (36/37) SLCTs and 4/4 GAB tested had a DICER1 mutation in an RNase IIIb domain hotspot; approximately half of these individuals had a predisposing germline DICER1 mutation. Metachronous SLCTs were seen in 3 individuals with germline DICER1 mutations. Other DICER1-associated conditions were seen in 19% of patients with SLCT or GAB. Three children of women with SLCT were diagnosed with PPB based on genetic testing and clinical screening during the course of this study. All were diagnosed with PPB in its earliest and most curable form (Type I), were treated with surgery alone, and are alive without evidence of disease.
Recognition of the distinct genetic basis for a group of these tumors improves precise classification in difficult cases and promotes mutation-based screening and early detection.
•DICER1 RNase IIIb mutations were identified in 36/37 SLCT's and 4/4 GABs sequenced.•Germline or mosaic mutations were found in more than half of those with SLCT.•Predisposing DICER1 mutations were associated with higher recurrence free survival.•DICER1 testing in women with SLCT facilitated screening of their children for PPB.•Three children were diagnosed with PPB in its earliest and most curable form.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Insulin secretion from β-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of β-cells elicit secretory defects associated with type-1 ...or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics. We show that this behavior is correlated with two subpopulations of insulin granules whose relative abundance is differentially shifted depending on diabetic model condition. The two types of granules have different release characteristics, distinct lipid and protein compositions, and package different secretory contents alongside insulin. This complexity of β-cell secretory physiology establishes a direct link between granule subpopulation and type of diabetes and leads to a revised model of secretory changes in the diabetogenic process.
Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), ...and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1–25%, 26–75%, and 76–100%. All type I PPBs showed 0–25% p53 expression compared to the higher p53 expression (>25%) in type III PPB (p < 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in >25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p < 0.0001). P53 expression was significantly associated with recurrence-free survival (p < 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
