Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .

Destabilizing NF1 variants act in a dominant negative manner through neurofibromin dimerization.

The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.

Novel uses of complement inhibitors in myasthenia gravis-Two case reports.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is a rare, life-threatening immune-related adverse effect (irAE) of immune checkpoint inhibitor (ICI) treatment. C5-complement inhibitors are effective treatments for acetylcholine receptor antibody (AChR ab) positive generalized MG. We describe the use of eculizumab/ravulizumab in two patients with MG receiving concomitant pembrolizumab. METHODS: This was a retrospective review of two medical records. RESULTS: Patient 1: An 80-year-old male with recurrent, non-muscle invasive transitional cell carcinoma of the bladder developed ICI-induced AChR ab positive MG (ICI-MG), myositis, and myocarditis 2 weeks after the first dose of pembrolizumab. Myositis responded to corticosteroids. MG responded to eculizumab, followed by ravulizumab. He died of metastatic cancer 8 months later. Patient 2: A 58-year-old male had refractory thymoma-associated AChR ab-positive MG, which responded to eculizumab. He developed metastatic Merkel cell cancer necessitating pembrolizumab. MG remained stable on eculizumab. He had no irAEs for 22 months, with positron emission tomographic resolution of cancer. He then developed mild, indolent retinal vasculitis, which responded to prednisone. Discontinuation of pembrolizumab for 5 months resulted in cancer recurrence; pembrolizumab was resumed with peri-infusion pulse prednisone. MG remained stable and he continues eculizumab. DISCUSSION: In the first patient, eculizumab, followed by ravulizumab, improved ICI-MG. In the second patient, eculizumab treatment may have had a prophylactic effect on the development of ICI-induced irAEs. The effect of complement inhibition on cancer outcomes of ICI therapy is unknown. A possible biologic basis for complement inhibitors in reducing irAEs of ICI, especially in the presence of underlying autoimmune disease, merits evaluation.

SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics.

Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps for RAF activation but the precise mechanisms and dynamics remain unclear. A ternary complex comprised of SHOC2, MRAS, and PP1 (SHOC2 complex) functions as a RAF S259 holophosphatase and gain-of-function mutations in SHOC2, MRAS, and PP1 that promote complex formation are found in Noonan syndrome. Here we show that SHOC2 complex-mediated S259 RAF dephosphorylation is critically required for growth factor-induced RAF heterodimerization as well as for MEK dissociation from BRAF. We also uncover SHOC2-independent mechanisms of RAF and ERK pathway activation that rely on N-region phosphorylation of CRAF. In DLD-1 cells stimulated with EGF, SHOC2 function is essential for a rapid transient phase of ERK activation, but is not required for a slow, sustained phase that is instead driven by palmitoylated H/N-RAS proteins and CRAF. Whereas redundant SHOC2-dependent and -independent mechanisms of RAF and ERK activation make SHOC2 dispensable for proliferation in 2D, KRAS mutant cells preferentially rely on SHOC2 for ERK signaling under anchorage-independent conditions. Our study highlights a context-dependent contribution of SHOC2 to ERK pathway dynamics that is preferentially engaged by KRAS oncogenic signaling and provides a biochemical framework for selective ERK pathway inhibition by targeting the SHOC2 holophosphatase.

Linking global drivers of agricultural trade to on-the-ground impacts on biodiversity.

Consumption of globally traded agricultural commodities like soy and palm oil is one of the primary causes of deforestation and biodiversity loss in some of the world's most species-rich ecosystems. However, the complexity of global supply chains has confounded efforts to reduce impacts. Companies and governments with sustainability commitments struggle to understand their own sourcing patterns, while the activities of more unscrupulous actors are conveniently masked by the opacity of global trade. We combine state-of-the-art material flow, economic trade, and biodiversity impact models to produce an innovative approach for understanding the impacts of trade on biodiversity loss and the roles of remote markets and actors. We do this for the production of soy in the Brazilian Cerrado, home to more than 5% of the world´s species. Distinct sourcing patterns of consumer countries and trading companies result in substantially different impacts on endemic species. Connections between individual buyers and specific hot spots explain the disproportionate impacts of some actors on endemic species and individual threatened species, such as the particular impact of European Union consumers on the recent habitat losses for the iconic giant anteater (Myrmecophaga tridactyla). In making these linkages explicit, our approach enables commodity buyers and investors to target their efforts much more closely to improve the sustainability of their supply chains in their sourcing regions while also transforming our ability to monitor the impact of such commitments over time.

Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina.

The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.

Evaluating a Pilot Culturally Sensitive Psychosocial Intervention on Posttraumatic Growth for Chinese American Breast Cancer Survivors.

This study investigated the potential benefit of a pilot culturally sensitive group support intervention, named Joy Luck Academy (JLA), in fostering posttraumatic growth among Chinese American breast cancer survivors. Eighty-six Chinese American breast cancer survivors participated in an eight-week single-arm pre-/post-test trial of an intervention program, which included educational lectures and peer mentor support. The JLA participants were compared with an independent sample of 109 Chinese American breast cancer survivors who went through routine care. Both groups completed baseline and eight-week follow-up assessments of the five facets of posttraumatic growth (meaningful interpersonal relationships, finding new possibilities in life, personal strength, appreciation of life, and spirituality). From baseline to follow-up, the JLA participants displayed significant improvements in the total score of posttraumatic growth, meaningful interpersonal relationships, appreciation of life, finding new possibilities in life, and personal strength. In contrast, the routine care participants showed no significant change in any of these outcome variables. The findings suggest the potential benefit of a culturally sensitive group support intervention in facilitating posttraumatic growth for Chinese American breast cancer survivors, indicating the need for a randomized controlled trial. The educational lectures and peer mentor support may be adapted to tailor the needs of other ethnic minority cancer patients.

A preliminary prospective study of health-related quality of life among Chinese-American breast cancer survivors.

PURPOSE: This study examined the predictors of health-related quality of life (HRQOL) and changes in HRQOL over a 1-year period among Chinese-American breast cancer survivors (BCS). METHODS: A two-wave longitudinal research design included participants from hospital-based cancer registries and community organizations in Los Angeles. Participants completed mailed questionnaires at baseline and 12-month follow-up. HRQOL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G v.4). Change in HRQOL was assessed using a 7-point meaningful change score. RESULTS: Participants were 73 Chinese-American BCS, a majority of whom were middle-aged (M = 54.6, SD = 9.2), lower income (63% < 45K), and diagnosed with stage I-II (83%) breast cancer. Regression analyses showed that multilevel contextual factors including general health perception, quality of care, life stress, and improvement in general health perception significantly predicted HRQOL at baseline and follow-up. The final model explained 72% of the variance of HRQOL. The examination of meaningful change indicated that improvement was reported by 32% (n = 22) and deterioration by 25% (n = 17); the majority indicated minimal change (43%, n = 30). Improvement was associated with increases in family communication, social support, and general health perception, while deterioration was associated with declines in social support, family communication, and general health perception. CONCLUSION: Findings indicate that among Chinese-American BCS, HRQOL is influenced by socioecological factors such as family communication and life stress. Results suggest that cancer survivorship outcomes research may benefit from theoretical foundations that examine the broader contextual dimensions that seem to impact and predict HRQOL. Implications for research are discussed.

Improvement in quality of life and psychological well-being associated with a culturally based psychosocial intervention for Chinese American breast cancer survivors.

PURPOSE: The purpose of this study was to investigate improvements in quality of life and psychological well-being among Chinese American breast cancer survivors who participated in a pilot community education and peer-mentor support program. METHODS: One hundred and twenty-nine Chinese American breast cancer survivors who recently completed treatment participated in eight cohorts of the program, Joy Luck Academy, which included weekly education and peer-mentor support sessions. The education sessions covered topics designed to help participants adjust to new life after breast cancer treatment. The peer-mentor support component was designed to provide social support. Quality of life and psychological well-being (e.g., depressive symptoms, anxiety, and low- and high-arousal positive and negative affect) were assessed at baseline and immediately after the intervention. RESULTS: Paired samples t tests indicated improvements in quality of life, low- and high-arousal positive affect, and reductions in depressive symptoms, anxiety, and low-arousal negative affect. CONCLUSION: Our findings suggest that a psychosocial group intervention may improve quality of life and psychological well-being among Chinese American breast cancer survivors. Our intervention has the potential to be applied to other ethnic-minority cancer survivors. Future randomized controlled trials are warranted.

An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth.

SHOC2 is mutated in Noonan syndrome and plays a key role in the activation of the ERK-MAPK pathway, which is upregulated in the majority of human cancers. SHOC2 functions as a PP1-regulatory protein and as an effector of MRAS. Here we show that SHOC2 and MRAS form a complex with SCRIB, a polarity protein with tumor suppressor properties. SCRIB functions as a PP1-regulatory protein and antagonizes SHOC2-mediated RAF dephosphorylation through a mechanism involving competition for PP1 molecules within the same macromolecular complex. SHOC2 function is selectively required for the malignant properties of tumor cells with mutant RAS, and both MRAS and SHOC2 play a key role in polarized migration. We propose that MRAS, through its ability to recruit a complex with paradoxical components, coordinates ERK pathway spatiotemporal dynamics with polarity and that this complex plays a key role during tumorigenic growth.

SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.

Dephosphorylation of the inhibitory "S259" site on RAF kinases (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme that dephosphorylates this S259 RAF site. MRAS and SHOC2 function as PP1 regulatory subunits providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit as membrane localization is required for efficient RAF dephosphorylation and ERK pathway regulation in cells. SHOC2's predicted structure shows remarkable similarities to the A subunit of PP2A, suggesting a case of convergent structural evolution with the PP2A heterotrimer. We have identified multiple regions in SHOC2 involved in complex formation as well as residues in MRAS switch I and the interswitch region that help account for MRAS's unique effector specificity for SHOC2-PP1. MRAS, SHOC2, and PPP1CB are mutated in Noonan syndrome, and we show that syndromic mutations invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development.

Biallelic RP1-associated retinal dystrophies: Expanding the mutational and clinical spectrum.

Purpose: To evaluate the phenotypic spectrum of autosomal recessive RP1-associated retinal dystrophies and assess genotypic associations. Methods: A retrospective multicenter study was performed of patients with biallelic RP1-associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and RP1 genotype were evaluated. Results: Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique RP1 variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of RP1 mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions: Biallelic RP1 mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic RP1 mutations.

Bending the Curve of Global Freshwater Biodiversity Loss: An Emergency Recovery Plan.

Despite their limited spatial extent, freshwater ecosystems host remarkable biodiversity, including one-third of all vertebrate species. This biodiversity is declining dramatically: Globally, wetlands are vanishing three times faster than forests, and freshwater vertebrate populations have fallen more than twice as steeply as terrestrial or marine populations. Threats to freshwater biodiversity are well documented but coordinated action to reverse the decline is lacking. We present an Emergency Recovery Plan to bend the curve of freshwater biodiversity loss. Priority actions include accelerating implementation of environmental flows; improving water quality; protecting and restoring critical habitats; managing the exploitation of freshwater ecosystem resources, especially species and riverine aggregates; preventing and controlling nonnative species invasions; and safeguarding and restoring river connectivity. We recommend adjustments to targets and indicators for the Convention on Biological Diversity and the Sustainable Development Goals and roles for national and international state and nonstate actors.

Benefits of a Psychosocial Intervention on Positive Affect and Posttraumatic Growth for Chinese American Breast Cancer Survivors: A Pilot Study.

Breast cancer survivors report persistent psychological and physical symptoms, which affect their quality of life and may challenge the recovery process. Due to social, cultural, and linguistic barriers, culturally sensitive care is largely unavailable for Chinese Americans, and their psychological needs are not often addressed. We aimed to investigate whether the Joy Luck Academy (JLA), a psychosocial intervention providing both information and peer support, was associated with positive adjustment among Chinese American breast cancer survivors. Thirty-nine Chinese American breast cancer survivors participated in a pilot psychosocial intervention. The educational materials and lectures were delivered in the participants' native language of Chinese. All of the educators and mentors shared the same linguistic and cultural background with the participants. The program utilized a community-based participatory research (CBPR) approach to further enhance the cultural sensitivity of the intervention. Participants' post-traumatic growth and positive affect were assessed before and after the intervention. The JLA showed an improvement in positive affect, and they had a greater appreciation for life. The intervention was found to be feasible, well-accepted, and beneficial for this population. Chinese American breast cancer survivors reported improved psychological health after attending the intervention. These findings encourage the development and implementation of psychosocial interventions for Chinese breast cancer survivors. Similar programs could be integrated into other ethnic or cultural communities.

Effects of cannabis and its components on the retina: a systematic review.

Purpose: Cannabis is the most prevalent drug in the world and its consumption is growing. Cannabinoid receptors are present in the human central nervous system. Recent studies show evidence of the effects of cannabinoids on the retina, and synthesising the results of these studies may be relevant for ophthalmologists. Thus, this review adopts standardised, systematic review methodology to investigate the effects of exposure to cannabis and components on the retina.Methods: We searched five online databases for the combined terms for outcome ("retina") and exposure ("cannabis"). Eligibility of studies were conducted by two independent reviewers, and risk of bias was assessed.Results: We retrieved 495 studies, screened 229 studies, assessed 52 studies for eligibility, and included 16 studies for qualitative analysis. The cannabinoids most frequently investigated were delta-9-tetrahydrocannabinol (THC), abnormal cannabidiol, synthetic cannabinoid, and cannabidiol (CDB). The outcomes most studied were neuroretinal dysfunction, followed by vascular effects. The studies also included investigation of neuroprotective and anti-inflammatory effects and teratogenic effects.Conclusions: This review suggests that cannabinoids may have an important role in retinal processing and function.

Protection of mice deficient in mature B cells from West Nile virus infection by passive and active immunization.

B cell activating factor receptor (BAFFR)-/- mice have a profound reduction in mature B cells, but unlike µMT mice, they have normal numbers of newly formed, immature B cells. Using a West Nile virus (WNV) challenge model that requires antibodies (Abs) for protection, we found that unlike wild-type (WT) mice, BAFFR-/- mice were highly susceptible to WNV and succumbed to infection within 8 to 12 days after subcutaneous virus challenge. Although mature B cells were required to protect against lethal infection, infected BAFFR-/- mice had reduced WNV E-specific IgG responses and neutralizing Abs. Passive transfer of immune sera from previously infected WT mice rescued BAFFR-/- and fully B cell-deficient µMT mice, but unlike µMT mice that died around 30 days post-infection, BAFFR-/- mice survived, developed WNV-specific IgG Abs and overcame a second WNV challenge. Remarkably, protective immunity could be induced in mature B cell-deficient mice. Administration of a WNV E-anti-CD180 conjugate vaccine 30 days prior to WNV infection induced Ab responses that protected against lethal infection in BAFFR-/- mice but not in µMT mice. Thus, the immature B cells present in BAFFR-/- and not µMT mice contribute to protective antiviral immunity. A CD180-based vaccine may promote immunity in immunocompromised individuals.

The subjective world of home care workers in dementia: an "order of worth" analysis.

The perspective of domiciliary workers is needed to recruit a high-quality workforce and meet growing demand. An English ethnographic study yielded extensive insights. To structure analysis of the study data, we apply a method developed by political theorists Boltanski and Thévenot that identifies key variables in different values systems. This "orders of worth" framework is used to map out the distinctive features of the subjective world of home carers. The results can be drawn on to formulate recruitment and retention policies, to design reward strategies or to ensure that training and education opportunities engage effectively with the workforce.

pRAD50: a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry.

BACKGROUND: AZD0156 and AZD6738 are potent and selective inhibitors of ataxia-telangiectasia-kinase (ATM) and ataxia-telangiectasia-mutated and Rad3-related (ATR), respectively, important sensors/signallers of DNA damage. METHODS: We used multiplexed targeted-mass-spectrometry to select pRAD50(Ser635) as a pharmacodynamic biomarker for AZD0156-mediated ATM inhibition from a panel of 45 peptides, then developed and tested a clinically applicable immunohistochemistry assay for pRAD50(Ser635) detection in FFPE tissue. RESULTS: We found moderate pRAD50 baseline levels across cancer indications. pRAD50 was detectable in 100% gastric cancers (n = 23), 99% colorectal cancers (n = 102), 95% triple-negative-breast cancers (TNBC) (n = 40) and 87.5% glioblastoma-multiformes (n = 16). We demonstrated AZD0156 target inhibition in TNBC patient-derived xenograft models; where AZD0156 monotherapy or post olaparib treatment, resulted in a 34-72% reduction in pRAD50. Similar inhibition of pRAD50 (68%) was observed following ATM inhibitor treatment post irinotecan in a colorectal cancer xenograft model. ATR inhibition, using AZD6738, increased pRAD50 in the ATM-proficient models whilst in ATM-deficient models the opposite was observed, suggesting pRAD50 pharmacodynamics post ATR inhibition may be ATM-dependent and could be useful to determine ATM functionality in patients treated with ATR inhibitors. CONCLUSION: Together these data support clinical utilisation of pRAD50 as a biomarker of AZD0156 and AZD6738 pharmacology to elucidate clinical pharmacokinetic/pharmacodynamic relationships, thereby informing recommended Phase 2 dose/schedule.

Expressive Writing Intervention Improves Quality of Life Among Chinese-American Breast Cancer Survivors: A Randomized Controlled Trial.

Background: Expressive writing interventions are shown to confer health benefits for Caucasian cancer survivors. However, few studies reported improved quality of life or studied ethnic minorities. Purpose: The study evaluated whether a culturally sensitive expressive writing intervention improved quality of life. Methods: Chinese-speaking breast cancer survivors (n = 136) in the USA were randomly assigned to one of three conditions to write three 30-min weekly essays: a cancer-fact condition to write about facts relevant to the cancer experience for three weeks; a self-regulation condition to write about deepest feelings at week 1, stress and coping at week 2, and finding benefits at week 3; or an enhanced self-regulation condition to write about stress and coping at week 1, deepest feelings at week 2, and finding benefits at week 3. Quality of life was assessed by Functional Assessment of Cancer Therapy at baseline, 1-, 3-, and 6-month follow-ups. Results: Growth curve models showed that quality of life was increased in the sample from baseline to the 6-month follow-up. The enhanced self-regulation condition had a large and statistically significant effect (d = 0.90, 95% CI [0.02, 1.687]), and the self-regulation condition had a small effect (d = 0.22, 95% CI [-0.79, 1.07]) on quality of life improvement compared with the cancer-fact group. Conclusion: Expressive writing is shown to be an effective intervention to improve quality of life for Chinese-American cancer survivors. Future efforts are warranted to disseminate and implement this low-dose and brief intervention in community and clinical settings. Clinical Trial Registration: NCT02946619.

Exploring characteristics, predictors, and consequences of fear of cancer recurrence among Asian-American breast cancer survivors.

BACKGROUND: To address the fear of cancer recurrence (FCR) research gap, we used prospective data to explore FCR predictors and FCR associations with health-related quality of life among Asian-American breast cancer survivors (BCS). METHODS: A total of 208 diverse Asian-American BCS completed T1 survey, and 137 completed T2 survey after 1 year. RESULTS: Fear of cancer recurrence scores (range = 0-4) were 2.01 at T1 and 1.99 at T2 reflecting low-to-moderate FCR. Scores of FCR were stable over the 1-year period (t(126) = .144, P = .886). Multiple regression analyses showed that Chinese women reported lower FCR both at T1 (t(193) = -2.92, P = .004) and T2 (t(128) = -2.56, P = .012) compared to other Asian women. Also, more positive health care experience at T1 predicted lower FCR at T2 (ß = -.18, P = .041). Controlling for other covariates, greater FCR at T1 predicted poorer outcomes 1 year later including lower physical (ß = -.31, P < .001), emotional (ß = -.37, P < .001) and functional (ß = -.16, P = .044) well-being and health-related quality of life specific to breast cancer at T2 (ß = -.31, P < .001). CONCLUSIONS: We found substantial consistencies and some divergences between our findings with Asian-American BCS and the existing literature. This prospective investigation reveals new information suggesting that Asian-American subgroup variation exists and health care system factors may influence FCR. Thus, FCR studies should consider Asian subgroupings, cultural aspects, ie, level of acculturation and health care system factors including provider-patient communication and treatment setting. Future research may benefit from contextualizing FCR within a broader distress framework to advance the science and practice of patient-centered and whole-person care.