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The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.

Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.

Before the U.S. Equal Employment Opportunity Commission may sue an employer for violating federal antidiscrimination law, it must first seek to engage the employer in conciliation. Conciliation offers employers an opportunity to resolve discrimination charges voluntarily in a setting analogous to settlement negotiations. In January 2021, EEOC promulgated a rule mandating that, as part of conciliation, employers be given certain information about the underlying charge. Congress subsequently rescinded the rule, however, citing its ostensible pro-employer/anti-worker bias. Congress’s nullification of the conciliation rule has generated considerable uncertainty not only for employers and workers but also for the Commission itself. That is because the rule was rescinded using the Congressional Review Act (CRA), which prohibits a rule from being issued “in substantially the same form” as one previously disapproved. Yet, the Act does not define “in substantially the same form” or otherwise specify what criteria should be used in assessing rules’ similarity. Nor has any court interpreted the phrase in the specific context of CRA. This article examines three possible methodologies for how the Commission might go about issuing a conciliation rule consistent with CRA— based on proposals from the academic literature, other agencies’ experience in reissuing disapproved rules, and procedures specified in CRA’s post-enactment legislative history—and demonstrates that while EEOC retains the discretion to issue a new conciliation rule, it is effectively barred from doing so absent further action by Congress. [ABSTRACT FROM AUTHOR]

Whereas Title VII has always contained an express exemption for religious organizations, ambiguities in the statutory text and legislative history render the exemption susceptible to three conflicting interpretations. This Article provides a detailed critique of each interpretation and demonstrates that while LGBTQ persons stand to retain meaningful employment protections under two Of the three interpretations, the third construction threatens to leave LGBTQ individuals-together with women, pregnant persons, and racial and ethnic minorities-vulnerable to discrimination in a host of non-ministerial, ostensibly secular positions. [ABSTRACT FROM AUTHOR]

Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase Cγ2 (PLCγ2 or PLCG2)--mutations in which are associated with autoinflammatory disorders and Alzheimer's disease--serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated endocannabinoid-eicosanoid cross-talk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal proinflammatory cytokine and chemokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in cross-talk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli. [ABSTRACT FROM AUTHOR]

Whereas the Supreme Court recently held that LGBTQ employment bias is actionable under Title VII as a form of sex discrimination, the statute does not protect persons working at small firms, i.e., businesses with fewer than fifteen employees. For these individuals, state law provides the exclusive means of redressing workplace bias, yet only twenty-two states prohibit discrimination on the basis of sexual orientation and gender identity. This article examines a subset of the twenty-eight states lacking explicit, LGBTQ-inclusive employment protections--those with antidiscrimination statutes applying to small firms otherwise exempt from Title VII--and demonstrates that, to varying degrees, these states would be justified in construing their statutes' existing bans on sex discrimination to protect LGBTQ workers. [ABSTRACT FROM AUTHOR]

Effective & Emerging Treatments in Pediatric Psychology By Anthony Spirito and Anne E. Kazak Oxford University Press, New York, 2006, 180 pp. DOI: 10.1037/1091-7527.24.4.471 Attention all health care providers interested [...]

Background: Rural communities throughout the United States are eager to recruit and retain family physicians. This study examined factors that may contribute to a medical student's decision to consider rural family medicine practice using the Community Apgar Questionnaire (CAQ).Methods: Third- and fourth-year medical students from 10 medical schools responded to a survey of 62 identified factors deemed to be present when assessing the strengths and challenges of recruiting family physicians to rural communities. Participants could also respond to six demographic questions. Factors were ranked based on importance to respondents and were compared using demographic information.Results: A total of 282 MS-3 and MS-4 students interested in family medicine from 10 US medical schools completed the survey (response rate 19.5%). Forty percent of participants anticipate practicing in a rural setting, followed by 31% for suburban and 29% for urban. The top three factors participants considered when anticipating a rural practice setting were spousal satisfaction, call frequency, and competition/collegiality. Additional differences were found across CAQ factors by future practice setting, gender, and location where the student was raised.Conclusions: Medical schools, rural preceptors, and rural communities may wish to consider highly rated factors found in the CAQ in the effort to increase the recruitment of family physicians interested in rural practice. [ABSTRACT FROM AUTHOR]

The article focuses on the U.S. Employment Non-Discrimination Act (ENDA) and mentions the need of executive order for legislation to protect LGBT persons against employment discrimination. Topics discussed include opposition of ENDA by legislators, U.S. President Barack Obama may extend explicit status-based protections to a significant number of LGBT workers and LGBT-related employment discrimination is also actionable as sex discrimination under Title VII of the Civil Rights Act of 1964.

This article provides the first comprehensive analysis of ENDA's shortcomings vis- ` a-vis Title VII of the Civil Rights Act of 1964. Whereas federal courts are increasingly likely to perceive LGBT-related employment discrimination as actionable sex discrimination under Title VII, the inclusion of gender identity protections in recent versions of ENDA has significantly diminished the bill's prospects for passage. This article contends that advocates should abandon their efforts to enact ENDA in favor of allowing Title VII's "sex" provision to continue on its LGBT-inclusive evolution. Title VII stands to provide LGBT persons with three distinct advantages relative to ENDA. First, Title VII allows plaintiffs to contest discrimination on either a disparate treatment or disparate impact theory. ENDA, in contrast, would permit only disparate treatment claims such that facially neutral employment practices having a disproportionately adverse effect on LGBT persons would not be actionable. Second, Title VII permits voluntary affirmative action plans whereas ENDA would prohibit preferential treatment on the basis of sexual orientation or gender identity even if LGBT persons were significantly underrepresented in a given workforce. Third, Title VII allows religious organizations to discriminate on the basis of religion but not race, color, ethnicity, or sex. ENDA, conversely, would allow religious organizations to discriminate on the basis of sexual orientation or gender identity without having to justify the discrimination on religious precepts. This article examines the feasibility of applying Title VII's protections to LGBT persons and concludes that, notwithstanding certain logistical difficulties in the short-run, LGBT individuals would benefit from the availability of disparate impact claims, voluntary affirmative action plans, and limited exemptions for religious organizations so that ENDA should be abandoned in favor of Title VII. [ABSTRACT FROM AUTHOR]

The article offers the author's insights on the decision of the U.S. Supreme Court in the foreign-squared (f-squared) securities fraud case Morrison versus National Australia Bank Ltd. The author says that the court uses the transactional test, where Section 10(b) of the Securities Exchange Act of 1934 applies to securities trading on U.S. stock exchanges and domestic transactions. He argues that the basis of the test is simple and direct means for disposing such claims.

No. Exercise doesn't decrease the frequency or severity of vasomotor menopausal symptoms in perimenopausal and postmenopausal women (strength of recommendation: A, systematic review of randomized controlled trials [RCTs] and consistent RCT). [ABSTRACT FROM AUTHOR]

An answer to a question on the effectiveness of exercise in decreasing the frequency or severity of vasomotor menopausal symptoms in women is presented.

A recent study evaluated the effectiveness of 3 direct oral anticoagulants and warfarin in patients with atrial fibrillation. So which agents came out on top?