Teflon promotes chromosomal recruitment of homolog conjunction proteins during Drosophila male meiosis.

Meiosis in males of higher dipterans is achiasmate. In their spermatocytes, pairing of homologs into bivalent chromosomes does not include synaptonemal complex and crossover formation. While crossovers preserve homolog conjunction until anaphase I during canonical meiosis, an alternative system is used in dipteran males. Mutant screening in Drosophila melanogaster has identified teflon (tef) as being required specifically for alternative homolog conjunction (AHC) of autosomal bivalents. The additional known AHC genes, snm, uno and mnm, are needed for the conjunction of autosomal homologs and of sex chromosomes. Here, we have analyzed the pattern of TEF protein expression. TEF is present in early spermatocytes but cannot be detected on bivalents at the onset of the first meiotic division, in contrast to SNM, UNO and MNM (SUM). TEF binds to polytene chromosomes in larval salivary glands, recruits MNM by direct interaction and thereby, indirectly, also SNM and UNO. However, chromosomal SUM association is not entirely dependent on TEF, and residual autosome conjunction occurs in tef null mutant spermatocytes. The higher tef requirement for autosomal conjunction is likely linked to the quantitative difference in the amount of SUM protein that provides conjunction of autosomes and sex chromosomes, respectively. During normal meiosis, SUM proteins are far more abundant on sex chromosomes compared to autosomes. Beyond promoting SUM recruitment, TEF has a stabilizing effect on SUM proteins. Increased SUM causes excess conjunction and consequential chromosome missegregation during meiosis I after co-overexpression. Similarly, expression of SUM without TEF, and even more potently with TEF, interferes with chromosome segregation during anaphase of mitotic divisions in somatic cells, suggesting that the known AHC proteins are sufficient for establishment of ectopic chromosome conjunction. Overall, our findings suggest that TEF promotes alternative homolog conjunction during male meiosis without being part of the final physical linkage between chromosomes.

Response to RL-225Ac in prostate cancer: Effect of prior treatment with RL-177Lu: A systematic review of the literature.

BACKGROUND: Targeted radionuclide therapy with Actinium-225-labeled prostate-specific membrane antigen agents (225Ac-PSMA) is currently being studied in clinical trials for patients with metastatic castration-resistant prostate cancer (mCRPC). Compared to ß-emitting therapeutic radionuclides, alpha-emitters (e.g., 225Ac) have a significantly higher linear energy transfer and significantly shorter range. As a result, alpha emitters could be expected to improve efficacy and reduce bystander toxicity. This systematic literature review was conducted to evaluate the impact of sequencing of 177Lu-PSMA and 225Ac-PSMA targeted radionuclide therapy (TRT) in mCRPC. METHODS: The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The searches were made using relevant keywords in the PubMed, Scopus, and Web of Science databases, and articles up to August 22, 2022, were included. Publications were excluded if they were duplicate publications, wrong study or publication format, or discussing a topic out of scope. Data on efficacy, toxicity, and health-related quality of life were extracted from the individual articles. The I2 index was used to measure the extent of heterogeneity amongst studies. In the studies that reported subgroup outcomes according to the prior status on 177Lu-PSMA TRT, pooled estimates of the main outcomes were generated through descriptive analysis. Quality assessment was performed using the Newark-Ottawa-scale. RESULTS: The study included 12 articles; 1 series was performed prospectively. In total, data of 329 patients were analyzed. About 40.1% (n = 132) of the included men were pretreated with 177Lu-PSMA TRT. Seven studies, including data of 212 individuals, were eligible for quantitative analysis based on reporting outcomes of the subgroups according to their prior status on 177Lu-PSMA TRT. >25% PSA decline after 225Ac-PSMA TRT was lower in individuals who received prior 177Lu-PSMA TRT (pooled median 42.7%) compared to those who did not (pooled median 15.4%). The pooled medians of the reported median progression-free survival and overall survival for pretreated versus not pretreated individuals was 4.3 versus 14.3 months and 11.1 versus 9.2 months, respectively. However, the outcomes for each individual study were reported inconsistently (I2 = 99.9%). None of the included studies stratified the report of adverse events or changes in health-related quality of life for the subgroups. CONCLUSIONS: 225Ac-PSMA TRT is an experimental treatment for men with mCRPC. There is limited data available from high-quality trials but so far PSMA-targeted TRT has demonstrated a low morbidity profile. Our review revealed that there is a possible decrease in efficacy of targeted alpha-particle therapy if individuals previously were exposed to 177Lu-PSMA TRT. However, the level of evidence is low. The underlying mechanism by which 177Lu-PSMA TRT might trigger possible radioresistance as well as randomized controlled trials are required to establish the therapeutic efficacy and safety of 225-Ac-PSMA TRT in men refractory to 177Lu-PSMA TRT.

Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic castration-resistant prostate cancer receiving prostate-specific membrane antigen targeted radionuclide therapy.

BACKGROUND: Neutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate-specific antigen (PSA) response and survival in men treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT). METHODS: Data of 180 men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in sequential prospective radionuclide clinical trials from 2002 to 2021 (utilizing 177Lu-J591, 90Y-J591, 177Lu-PSMA-617, or 225Ac-J591) were retrospectively analyzed. We used a logistic regression to determine the association between NLR and ≥50% PSA decline (PSA50) and a Cox proportional hazards model to investigate the association between NLR and overall survival (OS). RESULTS: A total of 94 subjects (52.2%) received 177Lu-J591, 51 (28.3%) 177Lu-PSMA-617, 28 (15.6%) 225Ac-J591, and 7 (3.9%) 90Y-J591. The median NLR of 3.75 was used as cut-off (low vs. high NLR; n = 90, respectively). On univariate analysis, NLR was not associated with PSA50 (HR 1.08; 95% confidence interval [CI] 0.99-1.17, p = 0.067). However, it was associated with worse OS (hazard ratio [HR] 1.06, 95% CI 1.02-1.09, p = 0.002), also after controlling for circulating tumor cell count and cancer and leukemia group B risk group (HR 1.05; 95% CI 1.003-1.11, p = 0.036). Men with high NLR were at a higher hazard of death from all causes (HR 1.43, 95% CI 1.05-1.94, p = 0.024). CONCLUSIONS: NLR provides prognostic information in the setting of patients with mCRPC receiving treatment with PSMA-TRT.

MNM and SNM maintain but do not establish achiasmate homolog conjunction during Drosophila male meiosis.

The first meiotic division reduces genome ploidy. This requires pairing of homologous chromosomes into bivalents that can be bi-oriented within the spindle during prometaphase I. Thereafter, pairing is abolished during late metaphase I, and univalents are segregated apart onto opposite spindle poles during anaphase I. In contrast to canonical meiosis, homologous chromosome pairing does not include the formation of a synaptonemal complex and of cross-overs in spermatocytes of Drosophila melanogaster. The alternative pairing mode in these cells depends on mnm and snm. These genes are required exclusively in spermatocytes specifically for successful conjunction of chromosomes into bivalents. Available evidence suggests that MNM and SNM might be part of a physical linkage that directly conjoins chromosomes. Here this notion was analyzed further. Temporal variation in delivery of mnm and snm function was realized by combining various transgenes with null mutant backgrounds. The observed phenotypic consequences provide strong evidence that MNM and SNM contribute directly to chromosome linkage. Premature elimination of these proteins results in precocious bivalent splitting. Delayed provision results in partial conjunction defects that are more pronounced in autosomal bivalents compared to the sex chromosome bivalent. Overall, our findings suggest that MNM and SNM cannot re-establish pairing of chromosomes into bivalents if provided after a chromosome-specific time point of no return. When delivered before this time point, they fortify preformed linkages in order to preclude premature bivalent splitting by the disruptive forces that drive chromosome territory formation during spermatocyte maturation and chromosome condensation during entry into meiosis I.

The combined importance of finite dimensions, anisotropy, and pre-stress in acoustoelastography.

Dynamic elastography, whether based on magnetic resonance, ultrasound, or optical modalities, attempts to reconstruct quantitative maps of the viscoelastic properties of biological tissue, properties that are altered by disease and injury, by noninvasively measuring mechanical wave motion in the tissue. Most reconstruction strategies that have been developed neglect boundary conditions, including quasistatic tensile or compressive loading resulting in a nonzero prestress. Significant prestress is inherent to the functional role of some biological tissues currently being studied using elastography, such as skeletal and cardiac muscle, arterial walls, and the cornea. In the present article, we review how prestress alters both bulk mechanical wave motion and wave motion in one- and two-dimensional waveguides. Key findings are linked to studies on skeletal muscle and the human cornea, as one- and two-dimensional waveguide examples. This study highlights the underappreciated combined acoustoelastic and waveguide challenge to elastography. Can elastography truly determine viscoelastic properties of a material when what it is measuring is affected by both these material properties and unknown prestress and other boundary conditions?

Development of a B-cell maturation antigen-specific T-cell antigen coupler receptor for multiple myeloma.

BACKGROUND AIMS: T cells engineered with synthetic receptors have delivered powerful therapeutic results for patients with relapsed/refractory hematologic malignancies. The authors have recently described the T-cell antigen coupler (TAC) receptor, which co-opts the endogenous T-cell receptor (TCR) and activates engineered T cells in an HLA-independent manner. Here the authors describe the evolution of a next-generation TAC receptor with a focus on developing a TAC-engineered T cell for multiple myeloma. METHODS: To optimize the TAC scaffold, the authors employed a bona fide antigen-binding domain derived from the B-cell maturation antigen-specific monoclonal antibody C11D5.3, which has been used successfully in the clinic. The authors first tested humanized versions of the UCHT1 domain, which is used by the TAC to co-opt the TCR. The authors further discovered that the signal peptide affected surface expression of the TAC receptor. Higher density of the TAC receptor enhanced target binding in vitro, which translated into higher levels of Lck at the immunological synapse and stronger proliferation when only receptor-ligand interactions were present. RESULTS: The authors observed that the humanized UCHT1 improved surface expression and in vivo efficacy. Using TAC T cells derived from both healthy donors and multiple myeloma patients, the authors determined that despite the influence of receptor density on early activation events and effector function, receptor density did not impact late effector functions in vitro, nor did the receptor density affect in vivo efficacy. CONCLUSIONS: The modifications to the TAC scaffold described herein represent an important step in the evolution of this technology, which tolerates a range of expression levels without impacting therapeutic efficacy.

Prostate-Specific Membrane Antigen (PSMA)-Targeted Radionuclide Therapies for Prostate Cancer.

PURPOSE OF REVIEW: Prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) is a promising investigational treatment for metastatic castration-resistant prostate cancer (mCRPC). This review describes the available data with PSMA TRT. RECENT FINDINGS: Conjugates used for PSMA TRT include antibodies or small molecules PSMA-radiolabeled with beta (most commonly 177Lu) or alpha emitters (commonly 225Ac). 177Lu-J591 demonstrated accurate targeting of known metastatic sites, based on post-treatment scintigraphy, in study populations that were not selected for PSMA expression, with evidence of dose-response and dose-limiting myelosuppression. Early phase studies of 177Lu-PSMA-617 have demonstrated favorable adverse event profiles and signs of clinical activity as evidenced by PSA responses and other short-term outcomes. A phase II randomized study of 177Lu-PSMA-617 showed a superior PSA50 response rate (66 vs 37%) over cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC selected by PSMA and FDG PET/CT scans. PSMA TRT is emerging as a promising investigational therapy for mCRPC. The first randomized data with 177Lu-PSMA-617 (phase 2) have been presented, and the first phase 3 trial has completed accrual with radiographic progression-free and overall survival as dual primary endpoints. Multiple additional phase 3 trials of PSMA-TRT are starting and studies investigating optimal patient selection and combination therapy continue.

Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes.

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

Vascular Nanomedicine: Current Status, Opportunities, and Challenges.

The term "nanotechnology" was coined by Norio Taniguchi in the 1970s to describe the manipulation of materials at the nano (10-9) scale, and the term "nanomedicine" was put forward by Eric Drexler and Robert Freitas Jr. in the 1990s to signify the application of nanotechnology in medicine. Nanomedicine encompasses a variety of systems including nanoparticles, nanofibers, surface nano-patterning, nanoporous matrices, and nanoscale coatings. Of these, nanoparticle-based applications in drug formulations and delivery have emerged as the most utilized nanomedicine system. This review aims to present a comprehensive assessment of nanomedicine approaches in vascular diseases, emphasizing particle designs, therapeutic effects, and current state-of-the-art. The expected advantages of utilizing nanoparticles for drug delivery stem from the particle's ability to (1) protect the drug from plasma-induced deactivation; (2) optimize drug pharmacokinetics and biodistribution; (3) enhance drug delivery to the disease site via passive and active mechanisms; (4) modulate drug release mechanisms via diffusion, degradation, and other unique stimuli-triggered processes; and (5) biodegrade or get eliminated safely from the body. Several nanoparticle systems encapsulating a variety of payloads have shown these advantages in vascular drug delivery applications in preclinical evaluation. At the same time, new challenges have emerged regarding discrepancy between expected and actual fate of nanoparticles in vivo, manufacturing barriers of complex nanoparticle designs, and issues of toxicity and immune response, which have limited successful clinical translation of vascular nanomedicine systems. In this context, this review will discuss challenges and opportunities to advance the field of vascular nanomedicine.

Lack of urea transporters, UT-A1 and UT-A3, increases nitric oxide accumulation to dampen medullary sodium reabsorption through ENaC.

Although the role of urea in urine concentration is known, the effect of urea handling by the urea transporters (UTs), UT-A1 and UT-A3, on sodium balance remains elusive. Serum and urinary sodium concentration is similar between wild-type mice (WT) and UT-A3 null (UT-A3 KO) mice; however, mice lacking both UT-A1 and UT-A3 (UT-A1/A3 KO) have significantly lower serum sodium and higher urinary sodium. Protein expression of renal sodium transporters is unchanged among all three genotypes. WT, UT-A3 KO, and UT-A1/A3 KO acutely respond to hydrochlorothiazide and furosemide; however, UT-A1/A3 KO fail to show a diuretic or natriuretic response following amiloride administration, indicating that baseline epithelial Na+ channel (ENaC) activity is impaired. UT-A1/A3 KO have more ENaC at the apical membrane than WT mice, and single-channel analysis of ENaC in split-open inner medullary collecting duct (IMCD) isolated in saline shows that ENaC channel density and open probability is higher in UT-A1/A3 KO than WT. UT-A1/A3 KO excrete more urinary nitric oxide (NO), a paracrine inhibitor of ENaC, and inner medullary nitric oxide synthase 1 mRNA expression is ~40-fold higher than WT. Because endogenous NO is unstable, ENaC activity was reassessed in split-open IMCD with the NO donor PAPA NONOate [1-propanamine-3-(2-hydroxy-2-nitroso-1-propylhydrazine)], and ENaC activity was almost abolished in UT-A1/A3 KO. In summary, loss of both UT-A1 and UT-A3 (but not UT-A3 alone) causes elevated medullary NO production and salt wasting. NO inhibition of ENaC, despite elevated apical accumulation of ENaC in UT-A1/A3 KO IMCD, appears to be the main contributor to natriuresis in UT-A1/A3 KO mice.

Treatment Features Associated with Youth Cognitive Behavioral Therapy Follow-Up Effects for Internalizing Disorders: A Meta-Analysis.

Our aim was to investigate whether four treatment features (i.e., the inclusion of parental involvement, goal-setting strategies, maintenance/relapse prevention sessions, the addition of booster sessions) were associated with posttreatment and follow-up effect size of youth cognitive behavioral therapies (yCBTs) for anxiety, depression, posttraumatic stress disorder, and obsessive-compulsive disorder in age groups spanning young children to adolescents. We conducted a random-effects meta-analysis of 106 yCBTs tested in 76 randomized clinical trials from the PracticeWise Database to examine average effects of yCBTs posttreatment and at a later follow-up assessment. We coded the use of parental involvement, goal setting, booster sessions, and maintenance/relapse prevention in each yCBT and conducted random-effects meta-regression analyses to investigate whether these treatment features were associated with yCBT effects at posttreatment as well as at follow-up. Overall, yCBTs produced large pre- to posttreatment effects (d = 1.05), 95% confidence interval [0.94, 1.15], and larger pre- to follow-up effects (d = 1.29), 95% confidence interval [1.18, 1.40]. Metaregression results indicated that parental involvement was significantly associated with larger pre- to posttreatment effect sizes as well as pre- to follow-up effect sizes. Booster sessions, goal setting, and maintenance/relapse prevention were not significantly related to effect sizes at posttreatment or follow-up. Parental involvement may be helpful for maximizing long-term effectiveness of yCBT. Future studies should investigate for whom and under what conditions inclusion of yCBT treatment features is related to the durability of treatment gains.

Posterior auricular muscle patch graft for exposed orbital implant.

The purpose of this article is to describe a surgical technique to repair an exposed orbital implant by posterior auricular muscle autograft. A retrospective review was conducted of four patients with an exposed orbital implant that were treated with a posterior auricular muscle graft. Four patients received posterior auricular muscle patch graft to the exposed orbital implant. The donor site healed with minimal scarring and remained well hidden. The graft incorporated fully into surrounding orbital tissue with no recurrent exposure at average of 13 month follow-up. The posterior auricular muscle autograft is a viable technique for repairing an exposed orbital implant.

3D printing for low cost, rapid prototyping of eyelid crutches.

Blepharoptosis or ptosis is a common and potentially debilitating clinical problem. Long-term surgical treatment for ptosis caused by progressive myopathies can be challenging due to potential recurrence and complications associated with facial muscle weakness. When surgical treatment is no longer effective, an eyelid crutch can be used as an alternative intervention. This report demonstrates how 3D printing was used to rapidly design, prototype, and manufacture new custom-fit eyelid crutches at a low cost.

Chronic lithium treatment induces novel patterns of pendrin localization and expression.

Prolonged lithium treatment is associated with various renal side effects and is known to induce inner medullary collecting duct (IMCD) remodeling. In animals treated with lithium, the fraction of intercalated cells (ICs), which are responsible for acid-base homeostasis, increases compared with renal principal cells (PCs). To investigate the intricacies of lithium-induced IMCD remodeling, male Sprague-Dawley rats were fed a lithium-enriched diet for 0,1, 2, 3, 6, 9, or 12 wk. Urine osmolality was decreased at 1 wk, and from 2 to 12 wk, animals were severely polyuric. After 6 wk of lithium treatment, approximately one-quarter of the cells in the initial IMCD expressed vacuolar H+-ATPase, an IC marker. These cells were localized in portions of the inner medulla, where ICs are not normally found. Pendrin, a Cl-/[Formula: see text] exchanger, is normally expressed only in two IC subtypes found in the convoluted tubule, the cortical collecting duct, and the connecting tubule. At 6 wk of lithium treatment, we observed various patterns of pendrin localization and expression in the rat IMCD, including a novel phenotype wherein pendrin was coexpressed with aquaporin-4. These observations collectively suggest that renal IMCD cell plasticity may play an important role in lithium-induced IMCD remodeling.

Kröhnke pyridines: Rapid and facile access to Mcl-1 inhibitors.

The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of α-pyridinium methyl ketone salts and α,ß-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Kröhnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i, i + 2 and i + 7 side chains of the BH3 α-helix.

Exploring Cultural Differences in Expressive Suppression and Emotion Recognition.

Previous research has shown that the habit of suppressing emotional expressions is associated with long-term, general reductions in social cognitive abilities and interpersonal adjustment. This may be because theoretically, habitual suppression requires the fixation of attention to the self instead of to others. The present research explored the association between the habitual tendency to suppress one's own emotions and accuracy in recognizing the emotions of others. Emotion recognition accuracy was tested across two tasks, a limited-channel task that presents limited emotional information and a multimodal full-channel task. We further explored cultural differences in this association given that expressive suppression may be normative for individuals of Asian descent due to cultural motivations toward social harmony and interdependence. Our findings revealed few cultural group differences. U.S.-born Asian Americans outperformed foreign-born Asian Americans and European Americans in limited-channel emotion recognition. However, the three groups did not differ in terms of interdependent self-construal, habitual emotion suppression, and full-channel emotion recognition ability. Interdependent self-construal was related to greater habitual suppression and emotion recognition accuracy in the full-channel task. Habitual emotion suppression was negatively related to limited-channel but not full-channel emotion recognition. There was no evidence of cultural differences in the link between habitual suppression and emotion recognition.

Managing In-Session "Surprises:" Provider Responses to Emergent Life Events during Evidence-Based Treatment Implementation.

This study aimed to: (1) pilot a psychotherapy coding system for provider responses to emergent life events (ELEs; unexpected events that have a significant negative impact on the client), (2) examine the impact of ELEs on evidence-based treatment (EBT) delivery in community settings. Raters coded 30 randomly-sampled EBT session recordings with and without reported ELEs. Inter-rater reliability and validity for the system were generally high. When an ELE occurred, providers were significantly less likely to deliver the EBT, and when they did, they rarely linked the EBT to the event. Findings highlight the potential for ELEs to disrupt EBT implementation.

Time for a Change: College Students' Preference for Technology-Mediated Versus Face-to-Face Help for Emotional Distress.

BACKGROUND: Even with recent advances in psychological treatments and mobile technology, online computerized therapy is not yet popular. College students, with ubiquitous access to technology, experiencing high distress, and often nontreatment seekers, could be an important area for online treatment dissemination. Finding ways to reach out to college students by offering psychological interventions through technology, devices, and applications they often use, might increase their engagement in treatment. INTRODUCTION: This study evaluates college students' reported willingness to seek help for emotional distress through novel delivery mediums, to play computer games for learning emotional coping skills, and to disclose personal information online. We also evaluated the role of ethnicity and level of emotional distress in help-seeking patterns. METHODS: A survey exploring our domains of interest and the Mental Health Inventory ([MHI] as mental health index) were completed by 572 students (mean age 18.7 years, predominantly Asian American, female, and freshmen in college). RESULTS: More participants expressed preference for online versus face-to-face professional help. We found no relationship between MHI and help-seeking preference. A third of participants were likely to disclose at least as much information online as face-to-face. Ownership of mobile technology was pervasive. Asian Americans were more likely to be nontreatment seekers than Caucasians. Most participants were interested in serious games for emotional distress. DISCUSSION: Our results suggest that college students are very open to creative ways of receiving emotional help such as playing games and seeking emotional help online, suggesting a need for online evidence-based treatments.

Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas.

Hypoxia-inducible factors (HIFs) control the cellular response to hypoxia and, when dysregulated, contribute to tumorigenesis. Previously, we identified 2 gain-of-function somatic mutations in patients presenting with multiple paragangliomas or somatostatinomas, and polycythemia. Here, we report 2 additional unique HIF2A mutations, which disrupt the hydroxylation domain recognized by prolyl hydroxylase domain-2 containing protein, leading to stabilization of HIF-2α and increased expression of hypoxia-related genes.