Development of the Mentoring in Undergraduate Research Survey.

Here we present the development of the Mentoring in Undergraduate Research Survey (MURS) as a measure of a range of mentoring experienced by undergraduate science researchers. We drafted items based on qualitative research and refined the items through cognitive interviews and expert sorting. We used one national dataset to evaluate the internal structure of the measure and a second national dataset to examine how responses on the MURS related to theoretically relevant constructs and student characteristics. Our factor analytic results indicate seven lower order forms of mentoring experiences: abusive supervision, accessibility, technical support, psychosocial support, interpersonal mismatch, sexual harassment, and unfair treatment. These forms of mentoring mapped onto two higher-order factors: supportive and destructive mentoring experiences. Although most undergraduates reported experiencing supportive mentoring, some reported experiencing absence of supportive as well as destructive experiences. Undergraduates who experienced less supportive and more destructive mentoring also experienced lower scientific integration and a dampening of their beliefs about the value of research. The MURS should be useful for investigating the effects of mentoring experienced by undergraduate researchers and for testing interventions aimed at fostering supportive experiences and reducing or preventing destructive experiences and their impacts.

Multidimensional Analysis of a Social Behavior Identifies Regression and Phenotypic Heterogeneity in a Female Mouse Model for Rett Syndrome.

Regression is a key feature of neurodevelopmental disorders such as autism spectrum disorder, Fragile X syndrome, and Rett syndrome (RTT). RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). It is characterized by an early period of typical development with subsequent regression of previously acquired motor and speech skills in girls. The syndromic phenotypes are individualistic and dynamic over time. Thus far, it has been difficult to capture these dynamics and syndromic heterogeneity in the preclinical Mecp2-heterozygous female mouse model (Het). The emergence of computational neuroethology tools allows for robust analysis of complex and dynamic behaviors to model endophenotypes in preclinical models. Toward this first step, we utilized DeepLabCut, a marker-less pose estimation software to quantify trajectory kinematics and multidimensional analysis to characterize behavioral heterogeneity in Het in the previously benchmarked, ethologically relevant social cognition task of pup retrieval. We report the identification of two distinct phenotypes of adult Het: Het that display a delay in efficiency in early days and then improve over days like wild-type mice and Het that regress and perform worse in later days. Furthermore, regression is dependent on age and behavioral context and can be detected in the initial days of retrieval. Together, the novel identification of two populations of Het suggests differential effects on neural circuitry, opens new avenues to investigate the underlying molecular and cellular mechanisms of heterogeneity, and designs better studies for stratifying therapeutics.

Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors.

PURPOSE: PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations. EXPERIMENTAL DESIGN: Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy. RESULTS: Among 828 patients, one or more deleterious BRCA1/2 mutations were detected in 60 (7.2%) patients, including germline (n = 42) and somatic (n = 18) mutations. Common coexisting mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%), and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline BRCA1/2-mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy. CONCLUSIONS: cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.

"Where's My Mentor?!" Characterizing Negative Mentoring Experiences in Undergraduate Life Science Research.

Undergraduate research experiences in science, technology, engineering, and mathematics fields are championed for promoting students' personal and professional development. Mentorship is an integral part of undergraduate research, as effective mentorship maximizes the benefits undergraduates realize from participating in research. Yet almost no research examines instances in which mentoring is less effective or even problematic, even though prior research on mentoring in workplace settings suggests negative mentoring experiences are common. Here, we report the results of a qualitative study to define and characterize negative mentoring experiences of undergraduate life science researchers. Undergraduate researchers in our study reported seven major ways they experienced negative mentoring: absenteeism, abuse of power, interpersonal mismatch, lack of career support, lack of psychosocial support, misaligned expectations, and unequal treatment. They described some of these experiences as the result of absence of positive mentoring behavior and others as actively harmful behavior, both of which they perceive as detrimental to their psychosocial and career development. Our results are useful to mentors for reflecting on ways their behaviors might be perceived as harmful or unhelpful. These findings can also serve as a foundation for future research aimed at examining the prevalence and impact of negative mentoring experiences in undergraduate research.

Stepwise development of a cancer care delivery research study to evaluate the prevalence of virus infections in cancer patients.

BACKGROUND: SWOG initiated a cancer care delivery research study of virus infection rates among newly diagnosed cancer patients. This study will inform viral screening guidelines in oncology clinics. METHODS: In a first step 'vanguard' phase, we evaluated the feasibility of multiple study procedures. Site investigators were surveyed to obtain feedback on study implementation. RESULTS: Much higher enrollment occurred at sites where all physicians participated and viral testing was performed as routine practice. These procedures will be required going forward. Additional protocol changes based on site investigator input were implemented. CONCLUSION: This multistep protocol design process illustrates how cancer care delivery research studies can adapt to real-world strategies and procedures that exist at community clinics where the predominance of cancer patients are treated.

(90)Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies.

BACKGROUND: For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering (90)Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine. METHODS: Fifty-eight patients with three (2-7) median prior treatments were treated on Arm A (N=29, (90)Y-clivatuzumab tetraxetan, weekly 6.5 mCi/m(2)doses×3, plus gemcitabine, weekly 200 mg/m(2) doses×4 starting 1 week earlier) or Arm B (N=29, (90)Y-clivatuzumab tetraxetan alone, weekly 6.5 mCi/m(2)doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated. RESULTS: Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3-9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan-Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29-0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1 year. CONCLUSIONS: Clinical studies of (90)Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.

The increasing labor force participation of older workers and its effect on the income of the aged.

The labor force participation rates of men and women aged 62-79 have notably increased since the mid-1990s. The result is a dramatic increase in the share of total money income attributable to earnings. For persons aged 65-69, the earnings share of total income increased from 28 percent in 1980 to 42 percent in 2009. For this age group in the late 1980s and early 1990s, Social Security benefits and earnings were roughly equal shares of total money income (about 30 percent); the earnings share is now more than 12 percentage points larger. When we focus on aged persons who receive Social Security benefits, earnings shares have increased markedly throughout the 62-79 age range since the early 1990s. We show that for aged persons with labor market earnings, those earnings have a large effect on their relative position in the distribution of annual money income of older Americans.

Long-term follow-up of a prospective trial of trimodality therapy of weekly paclitaxel, radiation, and androgen deprivation in high-risk prostate cancer with or without prior prostatectomy.

PURPOSE: Weekly paclitaxel, concurrent radiation, and androgen deprivation (ADT) were evaluated in patients with high-risk prostate cancer (PC) with or without prior prostatectomy (RP). METHODS AND MATERIALS: Eligible post-RP patients included: pathological T3 disease, or rising prostate-specific antigen (PSA) ≥ 0.5 ng/mL post-RP. Eligible locally advanced PC (LAPC) patients included: 1) cT2b-4N0N+, M0; 2) Gleason score (GS) 8-10; 3) GS 7 + PSA 10-20 ng/mL; or 4) PSA 20-150 ng/mL. Treatment included ADT (4 or 24 months), weekly paclitaxel (40, 50, or 60 mg/m(2)/wk), and pelvic radiation therapy (total dose: RP = 64.8 Gy; LAPC = 70.2 Gy). RESULTS: Fifty-nine patients were enrolled (LAPC, n = 29; RP, n = 30; ADT 4 months, n = 29; 24 months, n = 30; whites n = 29, African Americans [AA], n = 28). Baseline characteristics (median [range]) were: age 67 (45-86 years), PSA 5.9 (0.1-92.1 ng/mL), GS 8 (6-9). At escalating doses of paclitaxel, 99%, 98%, and 95% of doses were given with radiation and ADT, respectively, with dose modifications required primarily in RP patients. No acute Grade 4 toxicities occurred. Grade 3 toxicities were diarrhea 15%, urinary urgency/incontinence 10%, tenesmus 5%, and leukopenia 3%. Median follow-up was 75.3 months (95% CI: 66.8-82.3). Biochemical progression occurred in 24 (41%) patients and clinical progression in 11 (19%) patients. The 5- and 7-year OS rates were 83% and 67%. There were no differences in OS between RP and LAPC, 4- and 24-month ADT, white and AA patient categories. CONCLUSIONS: In addition to LAPC, to our knowledge, this is the first study to evaluate concurrent chemoradiation with ADT in high-risk RP patients. With a median follow-up of 75.3 months, this trial also represents the longest follow-up of patients treated with taxane-based chemotherapy with EBRT in high-risk prostate cancer. Concurrent ADT, radiation, and weekly paclitaxel at 40 mg/m(2)/week in RP patients and 60 mg/m(2)/week in LAPC patients is feasible and well-tolerated.

Assessing the performance of life-cycle portfolio allocation strategies for retirement saving: a simulation study.

This article examines the performance of four life-cycle portfolio allocation strategies through stochastic simulation based on observed U.S. asset returns during 1926-2008. Annual worker contributions to retirement savings accounts are based on the actual lifetime earnings histories maintained by the Social Security Administration for 12,871 workers born during 1915-1942. Each strategy's performance is evaluated primarily on the basis of the distributions of internal rates of return on investments calculated at the time of retirement. Comparisons are made with the performance of four other investment strategies that vary in terms of their exposure to stock and bond market risk. Life-cycle plans with larger portfolio weights assigned to equities have higher average returns, but those gains come at the cost of increased risk of infrequent bad outcomes.

Examining Social Security benefits as a retirement resource for near-retirees, by race and ethnicity, nativity, and disability status.

This article analyzes Social Security benefits as a retirement resource for selected subgroups of recent cohorts of near-retirees. The analysis therein examines the distribution of benefits among subgroups by (1) race and ethnicity, (2) nativity, and (3) disability status. We use improved data (actual earnings histories) to produce more accurate measures of benefits. We look at how the average values of several benefit measures, such as Social Security wealth and earnings replacement rates, differ among the selected subgroups and discuss reasons for these differences. This study finds that substantial differences in earnings levels and/or mortality levels among these subgroups interact with Social Security program provisions to produce sizable differences in the values of our benefit measures.

Phase II trial of gemcitabine/carboplatin followed by paclitaxel in patients with performance status=2,3 or other significant co-morbidity (HIV infection or s/p organ transplantation) in advanced non-small cell lung cancer.

INTRODUCTION: The role of chemotherapy in patients with advanced non-small cell lung cancer and poor performance status or who have HIV disease or organ transplantation is unclear. While survival appears to be enhanced, serious toxicity may occur. We evaluated the efficacy of sequential, dose attenuated carboplatin/gemcitabine followed by paclitaxel in patients with PS=2,3, HIV infection or after solid organ transplantation. PATIENTS AND METHODS: Chemotherapy naive patients with PS 2,3 or who were HIV positive or post solid organ transplantation were eligible. Treatment consisted of gemcitabine: 1000 mg/m(2) d 1,8 carboplatin: AUC=5 d 1 q 21d x 2 followed by paclitaxel 80 mg/m(2) q wk x 6 followed by a 2 week break and then repeated until progression. RESULTS: 47 patients were entered. Stage IIIb/IV: 8/39, PS 2/3=26/19, HIV infection=2, solid organ transplantation=2. 12 (25%) had brain metastases. Thirty-nine patients completed two cycles of carboplatin/gemcitabine and 29 pts received at least one cycle of paclitaxel. Overall response rate was 19% (95% CI 1.2-31.7%). Median event free, overall and 1-year survivals were 3.3 months, 5.8 months and 8.4%. Toxicity was moderate with 19% experiencing grade 4 neutropenia (11% with febrile neutropenia). CONCLUSIONS: Sequential carboplatin/gemcitabine to paclitaxel is well tolerated and active in this population. The survival seen is comparable to that of other regimens utilized in PS=2 patients with superior tolerability however, the prognosis for these patients is very poor even with treatment. This is the first trial to prospectively evaluate chemotherapy for patients with HIV disease or organ transplantation and NSCLC.

Testicular germ cell tumors.

PURPOSE OF REVIEW: Preclinical and clinical developments in germ cell tumors over the past year are summarized. RECENT FINDINGS: Attenuations in the rising incidence of testicular germ cell tumors are beginning to be observed in certain European populations. Additional data on predisposing factors related to race, estrogenic exposure, cryptorchidism, and infertility are becoming available. Significant work on the genetic and molecular alterations in tissue specimens and cell culture models of germ cell tumors continues. Additional treatment strategies for advanced stages of the disease are being evaluated. Cardiovascular and metabolic consequences of therapies in long-term testicular germ cell tumor survivors are being further clarified. Late relapses of successfully treated patients are also being increasingly recognized. SUMMARY: More effective treatments for intermediate risk, poor risk, and recurrent germ cell tumors need to be developed, while long-term toxicities of therapies need to be further modified. Given these challenges, active research on these fronts continues and remains a priority.

Cidofovir bladder instillation for the treatment of BK hemorrhagic cystitis after allogeneic stem cell transplantation.

We report a case of severe hemorrhagic cystitis after allogeneic transplantation in association with high BK viral load. After failure of aggressive hydration, platelet and blood transfusions, continuous bladder irrigation, and tapering of the immune suppression, we instilled cidofovir into the bladder, which resulted in decreased BK viral load and significant clinical improvement. Our case suggests that local cidofovir therapy for viral hemorrhagic cystitis is effective and well tolerated with no observed side effects.

Testicular germ cell tumors.

PURPOSE OF REVIEW: An overview of many of the preclinical and clinical developments in germ cell tumors over the past year is presented. RECENT FINDINGS: Recent epidemiologic studies show changes in the ethnic incidence of germ cell tumors; in particular, African-Americans have seen an increase. Additionally, risk factors for the development of germ cell tumors continue to be identified. Work on the molecular pathways involved in the progression to malignancy continues to expand. First line treatment for the disease is highly effective. In an effort to limit unnecessary treatments and treatment-related toxicities, risk-adapted adjuvant therapies are being explored in early stage germ cell tumors. Identification of more effective second-line treatments for advanced relapsing and refractory disease remains a priority. SUMMARY: Germ cell tumors are highly treatable, but significant challenges remain for recurrent and refractory disease. Recent studies on the molecular pathogenesis of germ cell tumors further highlight the complexity of the disease. As these processes are better understood, the therapeutic options will continue to evolve.

Mitogenic synergy through multilevel convergence of hepatocyte growth factor and interleukin-4 signaling pathways.

Hepatocyte growth factor (HGF) regulates various physiological and developmental processes in concert with other growth factors, cytokines and hormones. We examined interactions between cell signaling events elicited by HGF and the cytokine interleukin (IL)-4, in the IL-3-dependent murine myeloid cell line 32D transfected with the human HGF receptor, c-Met. HGF was a potent mitogen in these cells, and prevented apoptosis in response to IL-3 withdrawal. IL-4 showed modest anti-apoptotic activity, but no significant mitogenic activity. IL-4 synergistically enhanced HGF-stimulated DNA synthesis, whereas only additive prevention of apoptosis was observed. IL-4 did not enhance HGF-dependent tyrosine phosphorylation of c-Met or Shc. In contrast, HGF-stimulated activation of MAP kinases was enhanced by IL-4, suggesting that the IL-4 and HGF signaling pathways converge upstream of these events. Although phosphatidylinositol 3-kinase (PI3K) inhibitors diminished HGF-induced mitogenesis, anti-apoptosis, and MAP kinase activation, IL-4 enhanced HGF signaling persisted even in the presence of these inhibitors. IL-4 enhancement of HGF signaling was partially blocked in 32D/c-Met cells treated with inhibitors of MEK1 or c-Src kinases, completely blocked by expression of a catalytically inactive mutant of Janus kinase 3 (Jak3), and increased in 32D/c-Met cells overexpressing STAT6. Our results suggest that the IL-4 and HGF pathways converge at multiple levels, and that IL-4-dependent Jak3 and STAT6 activities modulate signaling events independent of PI3K to enhance HGF-dependent mitogenesis in myeloid cells, and possibly other common cellular targets.