Mechanistic and Treatment Implications of ΔNp63 Expression in a Rare Case of Metastatic Hidradenocarcinoma

Hidradenocarcinomas are rare, aggressive adnexal tumors of sweat gland origin that demonstrate a high potential for local recurrence, metastasis and poor outcome. These neoplasms can derive from preexisting clear cell hidradenomas, but more commonly appear de novo with the molecular events responsible for the pathogenesis currently unknown. Molecular markers of pathogenesis as well as effective forms of adjuvant chemotherapy are missing due to the lack of accurate diagnosis, paucity of cases and confusion with other visceral solid tumors. Here, we report a 37-year-old man who presented with a rapidly growing, painful palpable mass located in the right inguinal area. The patient was a nonsmoker, did not consume alcohol and had a medical history remarkable only for a lower abdominal superficial skin lesion in the same area that had been excised 11 years earlier. Although initially slow growing, the lesion eventually expanded, was surgically excised and was diagnosed as a hidradenoma. There was no family history of malignancy and the patient had not experienced any constitutional symptoms. We probed the immunohistochemical status and detected negative staining for the estrogen, progesterone and Her2 receptors, while strong, diffuse nuclear staining was seen in the majority of cells consistent with p53 overexpression. Similarly, strong nuclear reactivity was seen with p63 and p73 antibodies. The p63 gene contains 2 separate promoters which express at least 6 major transcripts that lead to 2 fundamentally different classes of proteins; 3 isoforms (TAp63α, β and γ) encode proteins that induce apoptosis, whereas the other 3 isoforms (ΔNp63α, β and γ) may exert inhibitory effects on p53. Interest in p63 stems from this ‘two genes in one’-concept. Importantly, the nuclear presence of ΔNp63 was detected widespread throughout the tumor. We have identified a subtype of hidradenocarcinomas that express ΔNp63 and uncovered an unforeseen commonality with triple-negative breast tumors. To our knowledge, this is the first report of a sweat gland tumor that displayed expression of both ΔNp63 and p73 and demonstrated a triple-negative receptor status. Such a link between 2 seemingly disparate tumor types indicates a mutual pathway of tumorigenesis and suggests the potential for common therapeutic regimens

Exposure of U.S. National Parks to land use and climate change 1900-2100

Many protected areas may not be adequately safeguarding biodiversity from human activities on surrounding lands and global change. The magnitude of such change agents and the sensitivity of ecosystems to these agents vary among protected areas. Thus, there is a need to assess vulnerability across networks of protected areas to determine those most at risk and to lay the basis for developing effective adaptation strategies. We conducted an assessment of exposure of U.S. National Parks to climate and land use change and consequences for vegetation communities. We first defined park protected-area centered ecosystems (PACEs) based on ecological principles. We then drew on existing land use, invasive species, climate, and biome data sets and models to quantify exposure of PACEs from 1900 through 2100. Most PACEs experienced substantial change over the 20th century (.740% average increase in housing density since 1940, 13% of vascular plants are presently nonnative, temperature increase of 18C/100 yr since 1895 in 80% of PACEs), and projections suggest that many of these trends will continue at similar or increasingly greater rates (255% increase in housing density by 2100, temperature increase of 2.58–4.58C/100 yr, 30% of PACE areas may lose their current biomes by 2030). In the coming century, housing densities are projected to increase in PACEs at about 82% of the rate of since 1940. The rate of climate warming in the coming century is projected to be 2.5–5.8 times higher than that measured in the past century. Underlying these averages, exposure of individual park PACEs to change agents differ in important ways. For example, parks such as Great Smoky Mountains exhibit high land use and low climate exposure, others such as Great Sand Dunes exhibit low land use and high climate exposure, and a few such as Point Reyes exhibit high exposure on both axes. The cumulative and synergistic effects of such changes in land use, invasives, and climate are expected to dramatically impact ecosystem function and biodiversity in national parks. These results are foundational to developing effective adaptation strategies and suggest policies to better safeguard parks under broad-scale environmental change

Assessment of Symptom, Disability, and Financial Trajectories in Patients Hospitalized for COVID-19 at 6 Months

IMPORTANCE: Individuals who survived COVID-19 often report persistent symptoms, disabilities, and financial consequences. However, national longitudinal estimates of symptom burden remain limited. OBJECTIVE: To measure the incidence and changes over time in symptoms, disability, and financial status after COVID-19-related hospitalization. DESIGN, SETTING, AND PARTICIPANTS: A national US multicenter prospective cohort study with 1-, 3-, and 6-month postdischarge visits was conducted at 44 sites participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Network\u27s Biology and Longitudinal Epidemiology: COVID-19 Observational (BLUE CORAL) study. Participants included hospitalized English- or Spanish-speaking adults without severe prehospitalization disabilities or cognitive impairment. Participants were enrolled between August 24, 2020, and July 20, 2021, with follow-up occurring through March 30, 2022. EXPOSURE: Hospitalization for COVID-19 as identified with a positive SARS-CoV-2 molecular test. MAIN OUTCOMES AND MEASURES: New or worsened cardiopulmonary symptoms, financial problems, functional impairments, perceived return to baseline health, and quality of life. Logistic regression was used to identify factors associated with new cardiopulmonary symptoms or financial problems at 6 months. RESULTS: A total of 825 adults (444 [54.0%] were male, and 379 [46.0%] were female) met eligibility criteria and completed at least 1 follow-up survey. Median age was 56 (IQR, 43-66) years; 253 (30.7%) participants were Hispanic, 145 (17.6%) were non-Hispanic Black, and 360 (43.6%) were non-Hispanic White. Symptoms, disabilities, and financial problems remained highly prevalent among hospitalization survivors at month 6. Rates increased between months 1 and 6 for cardiopulmonary symptoms (from 67.3% to 75.4%; P = .001) and fatigue (from 40.7% to 50.8%; P \u3c .001). Decreases were noted over the same interval for prevalent financial problems (from 66.1% to 56.4%; P \u3c .001) and functional limitations (from 55.3% to 47.3%; P = .004). Participants not reporting problems at month 1 often reported new symptoms (60.0%), financial problems (23.7%), disabilities (23.8%), or fatigue (41.4%) at month 6. CONCLUSIONS AND RELEVANCE: The findings of this cohort study of people discharged after COVID-19 hospitalization suggest that recovery in symptoms, functional status, and fatigue was limited at 6 months, and some participants reported new problems 6 months after hospital discharge

Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer.

PURPOSE: Cisplatin is widely used but highly ototoxic. Effects of cumulative cisplatin dose on hearing loss have not been comprehensively evaluated in survivors of adult-onset cancer. PATIENTS AND METHODS: Comprehensive audiological measures were conducted on 488 North American male germ cell tumor (GCT) survivors in relation to cumulative cisplatin dose, including audiograms (0.25 to 12 kHz), tests of middle ear function, and tinnitus. American Speech-Language-Hearing Association criteria defined hearing loss severity. The geometric mean of hearing thresholds (0.25 to 12 kHz) summarized overall hearing status consistent with audiometric guidelines. Patients were sorted into quartiles of hearing thresholds of age- and sex-matched controls. RESULTS: Increasing cumulative cisplatin dose (median, 400 mg/m(2); range, 200 to 800 mg/m(2)) was significantly related to hearing loss at 4, 6, 8, 10, and 12 kHz (P trends, .021 to \u3c .001): every 100 mg/m(2) increase resulted in a 3.2-dB impairment in age-adjusted overall hearing threshold (4 to 12 kHz; P \u3c .001). Cumulative cisplatin doses \u3e 300 mg/m(2) were associated with greater American Speech-Language-Hearing Association-defined hearing loss severity (odds ratio, 1.59; P = .0066) and worse normative-matched quartiles (odds ratio, 1.33; P = .093) compared with smaller doses. Almost one in five (18%) patients had severe to profound hearing loss. Tinnitus (40% patients) was significantly correlated with reduced hearing at each frequency (P \u3c .001). Noise-induced damage (10% patients) was unaffected by cisplatin dose (P = .59). Hypertension was significantly related (P = .0066) to overall hearing threshold (4 to 12 kHz) in age- and cisplatin dose-adjusted analyses. Middle ear deficits occurred in 22.3% of patients but, as expected, were not related to cytotoxic drug dosage. CONCLUSION: Follow-up of adult-onset cancer survivors given cisplatin should include routine inquiry for hearing status and tinnitus, referral to audiologists as clinically indicated, and hypertension control. Patients should be urged to avoid noise exposure, ototoxic drugs, and other factors that further damage hearing

Developing a Risk Model to Target High-Risk Preventive Interventions for Sexual Assault Victimization Among Female U.S. Army Soldiers

Sexual violence victimization is a significant problem among female U.S. military personnel. Preventive interventions for high-risk individuals might reduce prevalence but would require accurate targeting. We attempted to develop a targeting model for female Regular U.S. Army soldiers based on theoretically guided predictors abstracted from administrative data records. As administrative reports of sexual assault victimization are known to be incomplete, parallel machine learning models were developed to predict administratively recorded (in the population) and self-reported (in a representative survey) victimization. Capture–recapture methods were used to combine predictions across models. Key predictors included low status, crime involvement, and treated mental disorders. Area under the receiver operating characteristic curve was .83–.88. Between 33.7% and 63.2% of victimizations occurred among soldiers in the highest risk ventile (5%). This high concentration of risk suggests that the models could be useful in targeting preventive interventions, although final determination would require careful weighing of intervention costs, effectiveness, and competing risks

Phase 1 Gene Therapy for Duchenne Muscular Dystrophy Using a Translational Optimized AAV Vector

Efficient and widespread gene transfer is required for successful treatment of Duchenne muscular dystrophy (DMD). Here, we performed the first clinical trial using a chimeric adeno-associated virus (AAV) capsid variant (designated AAV2.5) derived from a rational design strategy. AAV2.5 was generated from the AAV2 capsid with five mutations from AAV1. The novel chimeric vector combines the improved muscle transduction capacity of AAV1 with reduced antigenic crossreactivity against both parental serotypes, while keeping the AAV2 receptor binding. In a randomized double-blind placebo-controlled phase I clinical study in DMD boys, AAV2.5 vector was injected into the bicep muscle in one arm, with saline control in the contralateral arm. A subset of patients received AAV empty capsid instead of saline in an effort to distinguish an immune response to vector versus minidystrophin transgene. Recombinant AAV genomes were detected in all patients with up to 2.56 vector copies per diploid genome. There was no cellular immune response to AAV2.5 capsid. This trial established that rationally designed AAV2.5 vector was safe and well tolerated, lays the foundation of customizing AAV vectors that best suit the clinical objective (e.g., limb infusion gene delivery) and should usher in the next generation of viral delivery systems for human gene transfer

FLAG Review 2021

We review lattice results related to pion, kaon, D-meson, B-meson, and nucleon physics with the aim of making them easily accessible to the nuclear and particle physics communities. More specifically, we report on the determination of the light-quark masses, the form factor $$f_+(0)$$ arising in the semileptonic $$K \rightarrow \pi$$ transition at zero momentum transfer, as well as the decay constant ratio $$f_K/f_\pi$$ and its consequences for the CKM matrix elements $$V_{us}$$ and $$V_{ud}$$. Furthermore, we describe the results obtained on the lattice for some of the low-energy constants of $$SU(2)_L\times SU(2)_R$$ and $$SU(3)_L\times SU(3)_R$$ Chiral Perturbation Theory. We review the determination of the $$B_K$$ parameter of neutral kaon mixing as well as the additional four B parameters that arise in theories of physics beyond the Standard Model. For the heavy-quark sector, we provide results for $$m_c$$ and $$m_b$$ as well as those for the decay constants, form factors, and mixing parameters of charmed and bottom mesons and baryons. These are the heavy-quark quantities most relevant for the determination of CKM matrix elements and the global CKM unitarity-triangle fit. We review the status of lattice determinations of the strong coupling constant $$\alpha _s$$. We consider nucleon matrix elements, and review the determinations of the axial, scalar and tensor bilinears, both isovector and flavor diagonal. Finally, in this review we have added a new section reviewing determinations of scale-setting quantities

The COMBREX Project: Design, Methodology, and Initial Results

© 2013 Brian P. et al.Prior to the “genomic era,” when the acquisition of DNA sequence involved significant labor and expense, the sequencing of genes was strongly linked to the experimental characterization of their products. Sequencing at that time directly resulted from the need to understand an experimentally determined phenotype or biochemical activity. Now that DNA sequencing has become orders of magnitude faster and less expensive, focus has shifted to sequencing entire genomes. Since biochemistry and genetics have not, by and large, enjoyed the same improvement of scale, public sequence repositories now predominantly contain putative protein sequences for which there is no direct experimental evidence of function. Computational approaches attempt to leverage evidence associated with the ever-smaller fraction of experimentally analyzed proteins to predict function for these putative proteins. Maximizing our understanding of function over the universe of proteins in toto requires not only robust computational methods of inference but also a judicious allocation of experimental resources, focusing on proteins whose experimental characterization will maximize the number and accuracy of follow-on predictions.COMBREX is funded by a GO grant from the National Institute of General Medical Sciences (NIGMS) (1RC2GM092602-01).Peer Reviewe