We present Keck/DEIMOS spectroscopy of stars in the recently discovered Milky Way satellites Hydra II, Pisces II, and Laevens 1. We measured a velocity dispersion of (ProQuest: Formulae and/or ...non-USASCII text omitted) for Pisces II, but we did not resolve the velocity dispersions of Hydra II or Laevens 1. We marginally resolved the metallicity dispersions of Hydra II and Pisces II but not Laevens 1. Furthermore, Hydra II and Pisces II obey the luminosity-metallicity relation for Milky Way dwarf galaxies (left angle bracketFe/Hright angle bracket = -2.02 + or - 0.08 and -2.45 + or - 0.07, respectively), whereas Laevens 1 does not (left angle bracketFe/Hright angle bracket = -1.68 + or - 0.05). The kinematic and chemical properties suggest that Hydra II and Pisces II are dwarf galaxies, and Laevens 1 is a globular cluster. We determined that two of the previously observed blue stars near the center of Laevens 1 are not members of the cluster. A third blue star has ambiguous membership. Hydra II has a radial velocity left angle bracketnuhelioright angle bracket = 303.1 + or - 1.4 km s super(-1), similar to the leading arm of the Magellanic stream. The mass-to-light ratio for Pisces II is (ProQuest: Formulae and/or non-USASCII text omitted) It is not among the most dark matter-dominated dwarf galaxies, but it is still worthy of inclusion in the search for gamma-rays from dark matter self-annihilation.
The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas ...its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.
We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.
Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval CI, 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 noninferiority margin, -8.5 percentage points). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.
A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).
Abstract
Objective
To update the “Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2009.
Participants
The ...participants include an Endocrine Society–appointed task force of nine experts, a methodologist, and a medical writer.
Evidence
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.
Consensus Process
Group meetings, conference calls, and e-mail communications enabled consensus. Endocrine Society committees, members and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines.
Conclusion
Gender affirmation is multidisciplinary treatment in which endocrinologists play an important role. Gender-dysphoric/gender-incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender. They require a safe and effective hormone regimen that will (1) suppress endogenous sex hormone secretion determined by the person’s genetic/gonadal sex and (2) maintain sex hormone levels within the normal range for the person’s affirmed gender. Hormone treatment is not recommended for prepubertal gender-dysphoric/gender-incongruent persons. Those clinicians who recommend gender-affirming endocrine treatments—appropriately trained diagnosing clinicians (required), a mental health provider for adolescents (required) and mental health professional for adults (recommended)—should be knowledgeable about the diagnostic criteria and criteria for gender-affirming treatment, have sufficient training and experience in assessing psychopathology, and be willing to participate in the ongoing care throughout the endocrine transition. We recommend treating gender-dysphoric/gender-incongruent adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with gonadotropin-releasing hormone agonists. Clinicians may add gender-affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age. For the care of peripubertal youths and older adolescents, we recommend that an expert multidisciplinary team comprised of medical professionals and mental health professionals manage this treatment. The treating physician must confirm the criteria for treatment used by the referring mental health practitioner and collaborate with them in decisions about gender-affirming surgery in older adolescents. For adult gender-dysphoric/gender-incongruent persons, the treating clinicians (collectively) should have expertise in transgender-specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient. We suggest maintaining physiologic levels of gender-appropriate hormones and monitoring for known risks and complications. When high doses of sex steroids are required to suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor both transgender males (female to male) and transgender females (male to female) for reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians should persistently monitor adverse effects of sex steroids. For gender-affirming surgeries in adults, the treating physician must collaborate with and confirm the criteria for treatment used by the referring physician. Clinicians should avoid harming individuals (via hormone treatment) who have conditions other than gender dysphoria/gender incongruence and who may not benefit from the physical changes associated with this treatment.
Gender affirmation is multidisciplinary treatment. Gender-dysphoric/gender-incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender.
Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct ...clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14⁺ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14⁺ epithelial tumor cell clusters disseminate collectively to colonize distant organs.
STAT3 transcription factor signaling in specific T helper cell differentiation has been well described, although the broader roles for STAT3 in lymphocyte memory are less clear. Patients with ...autosomal-dominant hyper-IgE syndrome (AD-HIES) carry dominant-negative STAT3 mutations and are susceptible to a variety of bacterial and fungal infections. We found that AD-HIES patients have a cell-intrinsic defect in the number of central memory CD4
+ and CD8
+ T cells compared to healthy controls. Naive T cells from AD-HIES patients had lower expression of memory-related transcription factors
BCL6 and
SOCS3, a primary proliferation defect, and they failed to acquire central memory-like surface phenotypes in vitro. AD-HIES patients showed a decreased ability to control varicella zoster virus (VZV) and Epstein-Barr virus (EBV) latency, and T cell memory to both of these viruses was compromised. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses.
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► Patients with AD-HIES have reduced number of central memory CD4 and CD8 T cells ► The reduction of central memory T cell numbers is T cell intrinsic ► Naive T cells from patients express decreased memory-related transcription factors ► HIES patients have an increased incidence of shingles and EBV viremia
We present metallicity distribution functions (MDFs) for the central regions of eight dwarf satellite galaxies of the Milky Way: Fornax, Leo I and II, Sculptor, Sextans, Draco, Canes Venatici I, and ...Ursa Minor. We use the published catalog of abundance measurements from the previous paper in this series. The measurements are based on spectral synthesis of iron absorption lines. For each MDF, we determine maximum likelihood fits for Leaky Box, Pre-Enriched, and Extra Gas (wherein the gas supply available for star formation increases before it decreases to zero) analytic models of chemical evolution. Although the models are too simplistic to describe any MDF in detail, a Leaky Box starting from zero metallicity gas fits none of the galaxies except Canes Venatici I well. The MDFs of some galaxies, particularly the more luminous ones, strongly prefer the Extra Gas Model to the other models. Only for Canes Venatici I does the Pre-Enriched Model fit significantly better than the Extra Gas Model. The best-fit effective yields of the less luminous half of our galaxy sample do not exceed 0.02 Z , indicating that gas outflow is important in the chemical evolution of the less luminous galaxies. We surmise that the ratio of the importance of gas infall to gas outflow increases with galaxy luminosity. Strong correlations of average Fe/H and metallicity spread with luminosity support this hypothesis.
Traditional theories of moral psychology emphasize reasoning and “higher cognition,” while more recent work emphasizes the role of emotion. The present fMRI data support a theory of moral judgment ...according to which both “cognitive” and emotional processes play crucial and sometimes mutually competitive roles. The present results indicate that brain regions associated with abstract reasoning and cognitive control (including dorsolateral prefrontal cortex and anterior cingulate cortex) are recruited to resolve difficult personal moral dilemmas in which utilitarian values require “personal” moral violations, violations that have previously been associated with increased activity in emotion-related brain regions. Several regions of frontal and parietal cortex predict intertrial differences in moral judgment behavior, exhibiting greater activity for utilitarian judgments. We speculate that the controversy surrounding utilitarian moral philosophy reflects an underlying tension between competing subsystems in the brain.
In some cases people judge it morally acceptable to sacrifice one person’s life in order to save several other lives, while in other similar cases they make the opposite judgment. Researchers have ...identified two general factors that may explain this phenomenon at the stimulus level: (1) the agent’s intention (i.e. whether the harmful event is intended as a means or merely foreseen as a side-effect) and (2) whether the agent harms the victim in a manner that is relatively “direct” or “personal”. Here we integrate these two classes of findings. Two experiments examine a novel personalness/directness factor that we call personal force, present when the force that directly impacts the victim is generated by the agent’s muscles (e.g., in pushing). Experiments 1a and b demonstrate the influence of personal force on moral judgment, distinguishing it from physical contact and spatial proximity. Experiments 2a and b demonstrate an interaction between personal force and intention, whereby the effect of personal force depends entirely on intention. These studies also introduce a method for controlling for people’s real-world expectations in decisions involving potentially unrealistic hypothetical dilemmas.
Over 30 states maintain criminal laws that expressly target people living with HIV. Thousands of people are prosecuted under these statutes, exposing them to decades of incarceration, thousands of ...dollars in fines, and state-sanctioned stigma. This broad pattern of discrimination based solely on HIV status - what this note terms serodiscrimination - is not supported by scientific evidence nor public health rationales. This note argues that many states' HIV-specific criminal laws violate the 'Americans with Disabilities Act' ban on discrimination by public entities. While previous constitutional challenges to these laws have fallen short, litigation under federal disability law offers a new pathway for reform.
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