Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection.

Ebola virus (EBOV) remains a public health threat. We performed a longitudinal study of B cell responses to EBOV in four survivors of the 2014 West African outbreak. Infection induced lasting EBOV-specific immunoglobulin G (IgG) antibodies, but their subclass composition changed over time, with IgG1 persisting, IgG3 rapidly declining, and IgG4 appearing late. Striking changes occurred in the immunoglobulin repertoire, with massive recruitment of naive B cells that subsequently underwent hypermutation. We characterized a large panel of EBOV glycoprotein-specific monoclonal antibodies (mAbs). Only a small subset of mAbs that bound glycoprotein by ELISA recognized cell-surface glycoprotein. However, this subset contained all neutralizing mAbs. Several mAbs protected against EBOV disease in animals, including one mAb that targeted an epitope under evolutionary selection during the 2014 outbreak. Convergent antibody evolution was seen across multiple donors, particularly among VH3-13 neutralizing antibodies specific for the GP1 core. Our study provides a benchmark for assessing EBOV vaccine-induced immunity.

Mobilization of innate and adaptive antitumor immune responses by the RNP-targeting antibody ATRC-101.

Immunotherapy approaches focusing on T cells have provided breakthroughs in treating solid tumors. However, there remains an opportunity to drive anticancer immune responses via other cell types, particularly myeloid cells. ATRC-101 was identified via a target-agnostic process evaluating antibodies produced by the plasmablast population of B cells in a patient with non-small cell lung cancer experiencing an antitumor immune response during treatment with checkpoint inhibitor therapy. Here, we describe the target, antitumor activity in preclinical models, and data supporting a mechanism of action of ATRC-101. Immunohistochemistry studies demonstrated tumor-selective binding of ATRC-101 to multiple nonautologous tumor tissues. In biochemical analyses, ATRC-101 appears to target an extracellular, tumor-specific ribonucleoprotein (RNP) complex. In syngeneic murine models, ATRC-101 demonstrated robust antitumor activity and evidence of immune memory following rechallenge of cured mice with fresh tumor cells. ATRC-101 increased the relative abundance of conventional dendritic cell (cDC) type 1 cells in the blood within 24 h of dosing, increased CD8+ T cells and natural killer cells in blood and tumor over time, decreased cDC type 2 cells in the blood, and decreased monocytic myeloid-derived suppressor cells in the tumor. Cellular stress, including that induced by chemotherapy, increased the amount of ATRC-101 target in tumor cells, and ATRC-101 combined with doxorubicin enhanced efficacy compared with either agent alone. Taken together, these data demonstrate that ATRC-101 drives tumor destruction in preclinical models by targeting a tumor-specific RNP complex leading to activation of innate and adaptive immune responses.

Estimating Gender Differences in the Association between Cognitive Resilience and Mild Cognitive Impairment Incidence.

INTRODUCTION: Recent evidence suggests that the influence of verbal intelligence and education on the onset of subjective cognitive decline may be modulated by gender, where education contributes less to cognitive resilience (CR) in women than in men. This study aimed to examine gender differences in the association between CR and mild cognitive impairment (MCI) incidence in an Australian population-based cohort. METHODS: We included 1,806 participants who had completed at least the first two waves and up to four waves of assessments in the Personality and Total Health (PATH) Through Life study (baseline: 49% female, male = 62.5, SD = 1.5, age range = 60-66 years). CR proxies included measures of educational attainment, occupation skill, verbal intelligence, and leisure activity. Discrete-time survival analyses were conducted to examine gender differences in the association between CR proxies and MCI risk, adjusting for age and apolipoprotein E4 status. RESULTS: Gender differences were only found in the association between occupation and MCI risk, where lower occupation skill was more strongly associated with higher risk in men than in women (odds ratio [OR] = 1.30, 95% confidence interval [CI] [1.07, 1.57]). In both genders, after adjusting for education and occupation, one SD increase in leisure activity was associated with lower MCI risk by 32% (OR = 0.76, 95% CI [0.65, 0.89]). Higher scores in verbal intelligence assessment were associated with reduced risk of MCI by 28% (OR = 0.78, 95% CI [0.69, 0.89]). CONCLUSION: Occupational experience may contribute to CR differently between genders. Life course cognitive engagement and verbal intelligence may be more protective against MCI than education and occupation for both men and women.

Cognition, function, and prevalent dementia in centenarians and near-centenarians: An individual participant data (IPD) meta-analysis of 18 studies.

INTRODUCTION: There are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100. METHODS: Participant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals ≥95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed. RESULTS: The mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI). DISCUSSION: Among the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.

A systematic review of the associations, mediators and moderators of life satisfaction, positive affect and happiness in near-centenarians and centenarians.

OBJECTIVE: Results from studies investigating life satisfaction, positive affect and happiness of near-centenarians (95+) and centenarians are inconsistent. This is the first systematic review to summarise the extant literature on the subjective well-being of this unique age group. METHOD: Seven electronic databases (PubMed, MEDLINE, EMBASE, PsycINFO, CINAHL, Web of Science and the Cochrane database for systematic reviews) were systematically searched. Subjective well-being was defined as life satisfaction, positive affect and happiness. A narrative synthesis of relevant articles was undertaken. RESULTS: Of 28 studies eligible for inclusion in this review, 20 predominantly examined life satisfaction, 11 positive affect and 4 happiness. Sex and other demographic variables were not significant predictors of subjective well-being. In contrast, greater perceived health was significantly associated with higher levels of life satisfaction and positive affect. Fatigue and visual impairment were significantly correlated with lower levels of life satisfaction and positive affect. However, there was considerable heterogeneity in the findings on physical, cognitive and social associations, mediators and moderators. CONCLUSION: The large discrepancy of results in the literature may be explained by methodological differences between studies. Centenarian research needs a clearer definition of life satisfaction, positive affect and happiness as their operationalisation is inconsistent. An international consortium of centenarian studies could facilitate cross-cultural comparisons on subjective well-being. Future research should be directed towards interventions that promote subjective well-being in the oldest-old.

The Impact of Radiologist Screening Mammogram Reading Volume on Performance in the Ontario Breast Screening Program.

PURPOSE: Although some studies have shown increasing radiologists' mammography volumes improves performance, there is a lack of evidence specific to digital mammography and breast screening program performance targets. This study evaluates the relationship between digital screening volume and meeting performance targets. METHODS: This retrospective cohort study included 493 radiologists in the Ontario Breast Screening Program who interpreted 1,762,173 screening mammograms in participants ages 50-90 between 2014 and 2016. Associations between annual screening volume and meeting performance targets for abnormal call rate, positive predictive value (PPV), invasive cancer detection rate (CDR), sensitivity, and specificity were modeled using mixed-effects multivariate logistic regression. RESULTS: Most radiologists read 500-999 (36.7%) or 1,000-1,999 (31.0%) screens annually, and 18.5% read ≥2,000. Radiologists who read ≥2,000 annually were more likely to meet abnormal call rate (OR = 3.85; 95% CI: 1.17-12.61), PPV (OR = 5.36; 95% CI: 2.53-11.34), invasive CDR (OR = 4.14; 95% CI: 1.50-11.46), and specificity (OR = 4.07; 95% CI: 1.89-8.79) targets versus those who read 100-499 screens. Radiologists reading 1,000-1,999 screens annually were more likely to meet PPV (OR = 2.32; 95% CI: 1.22-4.40), invasive CDR (OR = 3.36; 95% CI: 1.49-7.59) and specificity (OR = 2.00; 95% CI: 1.04-3.84) targets versus those who read 100-499 screens. No significant differences were observed for sensitivity. CONCLUSIONS: Annual reading volume requirements of 1,000 in Canada are supported as screening volume above 1,000 was strongly associated with achieving performance targets for nearly all measures. Increasing the minimum volume to 2,000 may further reduce the potential limitations of screening due to false positives, leading to improvements in overall breast screening program quality.

Pathways to Acceptance in Participants of Advanced Cancer Online Support Groups.

Background and Objectives: Individuals with cancer, especially advanced cancer, are faced with numerous difficulties associated with the disease, including an earlier death than expected. Those who are able to confront and accept the hardships associated with the disease in a way that aligns with their beliefs benefit from more positive psychological outcomes compared to those who are aware of their diagnosis but are unable to accept it. To date, there is limited research exploring factors contributing to illness and death acceptance in the context of advanced cancer in group therapy settings. Materials and Methods: The current study used a Directed Content Analysis approach on transcripts of online advanced cancer support groups to investigate if and how Yalom's existential factors played a role in the emergence of acceptance. Results: The online support group platform, combined with the help of facilitators, offered supportive environments for individuals seeking help with cancer-related distress by helping patients move towards acceptance. Some participants had already begun the process of accepting their diagnosis before joining the group, others developed acceptance during the group process, while a few continued to be distressed. Our analysis revealed the emergence of four themes related to illness acceptance: (1) Facilitator-Initiated Discussion, including sub-themes of Mindfulness, Relaxation and Imagery, Changing Ways of Thinking, and Spirituality; (2) Personal attitudes, including sub-themes of Optimism and Letting Go of Control; (3) Supportive Environment, including the sub-themes of Providing Support to Others and Receiving Support from Others; and (4) Existential Experience, which included sub-themes of Living with the Diagnosis for an Extended Amount of Time, Legacy and Death Preparations, and Appreciating life. Conclusions: With a paradigm shift to online delivery of psychological services, recognizing factors that contribute to acceptance when dealing with advanced cancer may help inform clinical practices. Future studies should explore patient acceptance longitudinally to inform whether it emerges progressively, which has been suggested by Kübler-Ross.

Feasibility and acceptability of i-Restoring Body Image after Cancer (i-ReBIC): A pilot trial for female cancer survivors.

OBJECTIVE: This pilot study aimed to evaluate the feasibility, acceptability, and psychosocial outcomes of a text-based online group therapy intervention, i-Restoring Body Image after Cancer (i-ReBIC). i-ReBIC was developed to reduce body image distress and psychosexual dysfunction among women diagnosed and treated for breast or gynecological cancer. METHODS: i-ReBIC was adapted from an empirically tested face-to-face group therapy intervention, ReBIC. Over the 8-week intervention, participants engaged in 90-minute weekly text-based online discussions. Each week, a new topic associated with reconnecting to the body, adjusting to a postcancer identity, and improving psychosexual functioning was addressed. Homework assignments included readings, guided imagery exercises, and journaling. RESULTS: Sixty women with cancer enrolled in the pilot study. Among them, 47 completed the intervention, and 44 filled out all prestudy and poststudy questionnaires. Ninety-three percent of participants (n = 41) were satisfied and reported that it met their expectations. Eighty percent of participants (n = 35) reported no technical difficulties during the intervention. Preoutcome and postoutcome measures on body image distress and experience of embodiment showed statistically significant improvements. Psychosexual distress and quality of life also showed improvements but were not statistically significant. CONCLUSIONS: This study suggests that i-ReBIC is feasible, well accepted, and effective in addressing persistent body image concerns experienced by women treated for breast or gynecological cancer. As an online group therapy, i-ReBIC can expand the reach of its original face-to-face intervention by mitigating barriers and improving access to care in a cost-effective manner.

Telephone versus in-person colorectal cancer risk and screening intervention for first-degree relatives: A randomized controlled trial.

BACKGROUND: Having a first-degree relative (FDR) with colorectal cancer (CRC) is a significant risk factor for CRC. Counseling for FDRs regarding CRC risk factors and personalized risk is important to improve knowledge and screening compliance. METHODS: A 3-arm randomized controlled trial compared tailored in-person and telephone CRC counseling interventions with controls among FDRs who were not mutation carriers for known hereditary cancer syndromes, but who were considered to be at an increased risk based on family history. It was hypothesized that both telephone and in-person approaches would increase CRC knowledge, screening adherence, perceived risk accuracy, and psychosocial functioning compared with controls. The authors anticipated greater satisfaction with the in-person approach. CRC knowledge, risk perception, psychosocial functioning, and intention to screen were assessed at baseline and at 2-week and 2-month follow-ups (primary endpoint). RESULTS: A total of 278 FDRs (mean age, 47.4 years, standard deviation, 11.38 years) participated. At baseline, participants reported low to moderate CRC knowledge and overestimations of risk. Screening adherence was 73.7%. At 2 months, participants in the in-person arm and telephone arm demonstrated improvements in knowledge and perceived risk and were not found to be statistically different from each other. However, when comparing each intervention with controls, knowledge in the in-person arm was found to be statistically significantly higher, but the difference between the telephone and control arms was not. Cancer-related stress reduced over time in all groups. Intervention benefits were maintained at 1 year. Baseline screening intent/adherence were high, and therefore did not reach statistically significant improvement. CONCLUSIONS: Tailored in-person or telephone formats for providing CRC risk counseling, incorporating behavioral interventions, appear to improve knowledge and risk perceptions, with high client satisfaction.

Symptom screening for constipation in oncology: getting to the bottom of the matter.

PURPOSE: This study seeks to determine whether specific screening for constipation will increase the frequency of clinician response within the context of an established symptom screening program. METHODS: A "constipation" item was added to routine Edmonton Symptom Assessment System (ESAS) screening in gynecologic oncology clinics during a 7-week trial period, without additional constipation-specific training. Chart audits were then conducted to determine documentation of assessment and intervention for constipation in three groups of patients, those who completed (1) ESAS (n = 477), (2) ESAS-C with constipation (n = 435), and (3) no ESAS (n = 511). RESULTS: Among patients who were screened for constipation, 17% reported moderate to severe symptoms. Greater constipation severity increased the likelihood of documented assessment (Z = 2.37, p = .018) and intervention (Z = 1.99, p = .048). Overall rates of documented assessment were 36%, with the highest assessment rate in the no ESAS group (χ2 = 9.505, p = .006), a group with the highest proportion of late-stage disease. No difference in the rate of assessment was found between the ESAS and ESAS-C groups. Overall rates for documentation of intervention were low, and did not differ between groups. CONCLUSIONS: Specific screening for constipation within an established screening program did not increase the documentation rate for constipation assessment or intervention. The inclusion of specific symptoms in multi-symptom screening initiatives should be carefully evaluated in terms of added value versus patient burden. Care pathways should include guidance on triaging results from multi-symptom screening, and clinicians should pay particular attention to patients who are missed from screening altogether, as they may be the most symptomatic group.

The prevalence and predictors of anxiety and depression in near-centenarians and centenarians: a systematic review.

BACKGROUND: Current research on the psychological health of near-centenarians (95-99 years old) and centenarians remains limited. Existing studies have mainly characterized their physical, cognitive, and social health. Results on the anxiety and depression of near-centenarians and centenarians (more than 95 years old) have been mixed with some studies, finding higher rates of anxiety and depression among those older than 95 years and others reporting no difference in rates compared with younger age groups. This study aims to synthesize the existing literature on the prevalence and predictors of anxiety and depression in near-centenarians and centenarians. METHOD: A systematic review was conducted using Ovid Medline, Embase, PsycINFO, CINAHL, SCOPUS, and the Cochrane database. Common and conflicting findings among the literature were examined. RESULTS: Thirty-eight studies met the inclusion criteria. Six studies examined the prevalence and predictors of anxiety, and 37 studies investigated the prevalence and predictors of depression. Five studies examined both anxiety and depression in the same sample. Prevalence data on anxiety and depression varied significantly, as did comparisons with rates in younger populations. Findings on predictors of anxiety and depression were contradictory. CONCLUSION: There is a large degree of heterogeneity among studies of centenarians' psychological status. Findings conflict on the prevalence and predictors of anxiety and depression and rates compared with younger age groups. Variation in findings may result from the different inclusion criteria, sampling methods, and measurement tools. Better harmonization of centenarian study methodologies may improve consistency of findings to aid in developing clinical interventions.

The psychological health of 207 near-centenarians (95-99) and centenarians from the Sydney Centenarian Study.

OBJECTIVE: While near-centenarians (95-99) and centenarians are the fastest growing sectors of the population in many countries, few studies have investigated their psychological health. We aimed to compare levels of psychological distress and life satisfaction in individuals aged 95 or above (95+) with younger age groups and identify the factors associated with psychological distress and life satisfaction in near-centenarians and centenarians. METHODS: We assessed the physical, cognitive, social and psychological health of 207 participants aged 95+ in the Sydney Centenarian Study. Psychological distress and life satisfaction were rated on the Kessler Psychological Distress Scale (K10) and Satisfaction with Life Scale, respectively. Cross-sectional univariate comparisons were performed with participants aged 70-90 years from the Sydney Memory and Ageing Study. Factors associated with psychological distress and life satisfaction among Sydney Centenarian Study participants were examined using multiple regression analyses. RESULTS: In Sydney Centenarian Study and Memory and Ageing Study, mean K10 scores were 15.3 (±5.9) and 13.4 (±3.6), and clinical levels of psychological distress (K10 ⩾ 20) were 19% and 7%, respectively. Sydney Centenarian Study participants demonstrated significantly higher levels and rates of psychological distress (t = 3.869, p < 0.001; χ2 = 27.331, p < 0.001). In Sydney Centenarian Study, more psychotropic medications and having fewer relatives and friends were associated with higher psychological distress. Sydney Centenarian Study participants reported significantly higher levels of life satisfaction than Memory and Ageing Study participants, mean scores 6.0 (±1.5) and 5.6 (±1.3); t = 5.835, p < 0.001. Lower Mini-Mental State Examination scores and having fewer relatives and friends were associated with lower life satisfaction in Sydney Centenarian Study. CONCLUSION: Despite showing higher levels of psychological distress in the prior 4 weeks than younger age groups, near-centenarians and centenarians remained highly satisfied with their overall lives. The identification of risk and protective factors for psychological distress and life satisfaction provides opportunities for interventions to maintain good psychological health in this vulnerable population.

Non-progressing cancer patients have persistent B cell responses expressing shared antibody paratopes that target public tumor antigens.

There is significant debate regarding whether B cells and their antibodies contribute to effective anti-cancer immune responses. Here we show that patients with metastatic but non-progressing melanoma, lung adenocarcinoma, or renal cell carcinoma exhibited increased levels of blood plasmablasts. We used a cell-barcoding technology to sequence their plasmablast antibody repertoires, revealing clonal families of affinity matured B cells that exhibit progressive class switching and persistence over time. Anti-CTLA4 and other treatments were associated with further increases in somatic hypermutation and clonal family size. Recombinant antibodies from clonal families bound non-autologous tumor tissue and cell lines, and families possessing immunoglobulin paratope sequence motifs shared across patients exhibited increased rates of binding. We identified antibodies that caused regression of, and durable immunity toward, heterologous syngeneic tumors in mice. Our findings demonstrate convergent functional anti-tumor antibody responses targeting public tumor antigens, and provide an approach to identify antibodies with diagnostic or therapeutic utility.

A randomized controlled trial of a supportive expressive group intervention for women with a family history of breast cancer.

OBJECTIVE: Women with a family history of breast cancer (BC) often overestimate their BC risk. Heightened psychological distress may interfere with risk comprehension and screening adherence. The primary purpose of this study was to test the efficacy of a 12-week manual-based supportive-expressive (SE) group intervention for this population. METHODS: Using a randomized control trial design, this study compared two interventions: a standard risk-counseling arm (RC) compared with that plus SE group intervention. The primary study outcome was BC anxiety. Secondary outcomes included psychosocial functioning, risk comprehension, BC knowledge, and screening behaviors. RESULTS: A total of 161 women with a family history of BC were randomized into SE (N = 108) or RC (N = 53). Participants in both study arms significantly improved on measures of BC anxiety, psychosocial functioning, risk comprehension, and BC knowledge, with no statistical difference between study arms. Benefits were sustained at 1 year. BC screening rates were high in both arms at baseline and follow-up. CONCLUSIONS: SE group therapy as an added intervention to the risk counseling was well-received, however, did not demonstrate superiority to RC alone. Future studies on treatment matching are needed to further our understanding of interventions that can support women with a family history of BC to work through residual issues, including loss and grief.

Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration.

Regulation of adult stem cells (SCs) is fundamental for organ maintenance and tissue regeneration. On the body surface, different ectodermal organs exhibit distinctive modes of regeneration and the dynamics of their SC homeostasis remain to be unraveled. A slow cycling characteristic has been used to identify SCs in hair follicles and sweat glands; however, whether a quiescent population exists in continuously growing nails remains unknown. Using an in vivo label retaining cells (LRCs) system, we detected an unreported population of quiescent cells within the basal layer of the nail proximal fold, organized in a ring-like configuration around the nail root. These nail LRCs express the hair stem cell marker, keratin 15 (K15), and lineage tracing show that these K15-derived cells can contribute to both the nail structure and peri-nail epidermis, and more toward the latter. Thus, this stem cell population is bifunctional. Upon nail plucking injury, the homeostasis is tilted with these SCs dominantly delivering progeny to the nail matrix and differentiated nail plate, demonstrating their plasticity to adapt to wounding stimuli. Moreover, in vivo engraftment experiments established that transplanted nail LRCs can actively participate in functional nail regeneration. Transcriptional profiling of isolated nail LRCs revealed bone morphogenetic protein signaling favors nail differentiation over epidermal fate. Taken together, we have found a previously unidentified ring-configured population of bifunctional SCs, located at the interface between the nail appendage organ and adjacent epidermis, which physiologically display coordinated homeostatic dynamics but are capable of rediverting stem cell flow in response to injury.

Feasibility and diagnostic accuracy of the Patient-Reported Outcomes Measurement Information System (PROMIS) item banks for routine surveillance of sleep and fatigue problems in ambulatory cancer care.

BACKGROUND: Routine screening for problematic symptoms is emerging as a best practice in cancer systems globally. The objective of this observational study was to assess the feasibility and diagnostic accuracy of Patient-Reported Outcomes Measurement Information System (PROMIS) computerized adaptive testing (CAT) for fatigue and sleep-disturbance items compared with legacy measures in routine ambulatory cancer care. METHODS: Patients who attended outpatient clinics at the Princess Margaret Cancer Center completed PROMIS CAT item banks and legacy measures (the Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scale and the Insomnia Severity Index [ISI]) using tablet computers during clinic visits. The completion rates, patient acceptability, and diagnostic accuracy of PROMIS CAT were evaluated against legacy measures using receiver operating characteristic (ROC) curve analysis. RESULTS: Participants consisted of 336 patients (mean age ± standard deviation, 57.4 ± 15.7 years; 55% females; 75% Caucasian). Over 98% of patients did not find symptom screening was burdensome, although only 65% were willing to complete the survey at every visit. PROMIS CAT scores were significantly correlated with both FACIT-Fatigue scores (r = -0.83) and ISI scores (r = -0.57; p < 0.0001 for all). Areas under the curve (AUC) by ROC analysis for fatigue were 0.946 using the FACIT-Fatigue cutoff ≤30, 0.910 for sleep disturbance, and 0.922 for sleep impairment using the ISI cutoff ≥15. The recommended T-score cut-off for PROMIS CAT Fatigue was 57, Sleep Disturbance was 57, and Sleep Impairment was 57. CONCLUSIONS: The current results support the feasibility and accuracy of PROMIS CAT and its potential for use in routine ambulatory cancer care. Future research will assess feedback of these data to clinicians and evaluate effects on earlier identification of and intervention for these problems. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2906-2917. © 2016 American Cancer Society.

Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation.

Hair follicles facilitate the study of stem cell behavior because stem cells in progressive activation stages, ordered within the follicle architecture, are capable of cyclic regeneration. To study the gene network governing the homeostasis of hair bulge stem cells, we developed a Keratin 15-driven genetic model to directly perturb molecular signaling in the stem cells. We visualize the behavior of these modified stem cells, evaluating their hair-regenerating ability and profile their molecular expression. Bone morphogenetic protein (BMP)-inactivated stem cells exhibit molecular profiles resembling those of hair germs, yet still possess multipotentiality in vivo. These cells also exhibit up-regulation of Wnt7a, Wnt7b, and Wnt16 ligands and Frizzled (Fzd) 10 receptor. We demonstrate direct transcriptional modulation of the Wnt7a promoter. These results highlight a previously unknown intra-stem cell antagonistic competition, between BMP and Wnt signaling, to balance stem cell activity. Reduced BMP signaling and increased Wnt signaling tilts each stem cell toward a hair germ fate and, vice versa, based on a continuous scale dependent on the ratio of BMP/Wnt activity. This work reveals one more hierarchical layer regulating stem cell homeostasis beneath the stem cell-dermal papilla-based epithelial-mesenchymal interaction layer and the hair follicle-intradermal adipocyte-based tissue interaction layer. Although hierarchical layers are all based on BMP/Wnt signaling, the multilayered control ensures that all information is taken into consideration and allows hair stem cells to sum up the total activators/inhibitors involved in making the decision of activation.

Combination of SAHA and bortezomib up-regulates CDKN2A and CDKN1A and induces apoptosis of Epstein-Barr virus-positive Wp-restricted Burkitt lymphoma and lymphoblastoid cell lines.

Epstein-Barr virus (EBV) latent proteins exert anti-apoptotic effects on EBV-transformed lymphoid cells by down-regulating BCL2L11 (BIM), CDKN2A (p16(INK4A) ) and CDKN1A (p21(WAF1) ). However, the potential therapeutic effects of targeting these anti-apoptotic mechanisms remain unexplored. Here, we tested both in vitro and in vivo effects of the combination of histone deacetylase (HDAC) and proteasome inhibitors on the apoptosis of six endemic Burkitt lymphoma (BL) lines of different latency patterns (types I and III and Wp-restricted) and three lymphoblastoid cell lines (LCLs). We found that the combination of HDAC and proteasome inhibitors (e.g. SAHA/bortezomib) synergistically induced the killing of Wp-restricted and latency III BL and LCLs but not latency I BL cells. The synergistic killing was due to apoptosis, as evidenced by the high percentage of annexin V positivity and strong cleavage of PARP1 (PARP) and CASP3 (caspase-3). Concomitantly, SAHA/bortezomib up-regulated the expression of CDKN2A and CDKN1A but did not affect the level of BCL2L11 or BHRF1 (viral homologue of BCL2). The apoptotic effects were dependent on reactive oxygen species generation. Furthermore, SAHA/bortezomib suppressed the growth of Wp-restricted BL xenografts in nude mice. This study provides the rationale to test the novel application of SAHA/bortezomib on the treatment of EBV-associated Wp-restricted BL and post-transplant lymphoproliferative disorder.

Understanding Elderly Chinese Cancer Patients in a Multicultural Clinical Setting: Embracing Mortality and Addressing Misperceptions of Vulnerability.

Chinese patients face higher risks of gastrointestinal (GI) cancers and greater cancer-related deaths than Canadian-born patients. The older population encounters barriers to quality healthcare, impacting their well-being and survival. Previous studies highlighted Chinese immigrant perceptions of not requiring healthcare support. During the COVID-19 pandemic, their underutilization of healthcare services garnered attention. The present study explores the experiences of older Chinese cancer patients to improve culturally sensitive cancer care. A total of twenty interviews carried out in Cantonese and Mandarin were conducted with Chinese immigrants, aged 60 or above, diagnosed with Stage 3 or 4 GI cancer. These interviews were transcribed verbatim, translated, and subjected to qualitative descriptive analysis. Among older Chinese immigrant patients, a phenomenon termed "Premature Acceptance: Normalizing Death and Dying" was observed. This involved four key themes: 1. acceptance and letting go, 2. family first, 3. self-sufficiency, and 4. barriers to supportive care. Participants displayed an early acceptance of their own mortality, prioritizing family prosperity over their own quality of life. Older Chinese patients normalize the reality of facing death amidst cancer. They adopt a pragmatic outlook, acknowledging life-saving treatments while willingly sacrificing their own support needs to ease family burdens. Efforts to enhance health literacy require culturally sensitive programs tailored to address language barriers and differing values among this population. A strengths-based approach emphasizing family support and practical aspects of care may help build resilience and improve symptom management, thereby enhancing their engagement with healthcare services.