Household Dependence on Forest Resources in the Luki Biosphere Reserve, Democratic Republic of CONGO.

This study was aimed at examining the contribution of forest products to rural livelihoods and the socio-economic factors that influence household forest dependence in the Luki Biosphere Reserve. A structured questionnaire poll of 193 households randomly chosen from two enclaves in the Luki Biosphere Reserve, and focus group discussions were used to gather the data. For data analysis, a binary logistic regression model was used. The study revealed a substantial contribution of forest products to household livelihood based on household wealth strata and the gender of the household head. The contribution of forest income has been found to be higher for poor households than to other wealth categories, although their mean income from forest was low. However, the present research further revealed that household forest dependence was significantly determined by socioeconomic factors such as length of residency, age, sex, education, employment and household size. Compared to their elderly counterparts, the youth were probably more dependent on forest products. Therefore, there should be increased capacity-building efforts among the young people to enable them enlighten the local communities about the need for sustainable forest management. Meanwhile, highly educated people were observed to be less dependent on forests. The findings of this research provides empirical evidence from the Mayombe tropical forest, thus contributing to the growth of knowledge on the impact of socioeconomic factors on the household dependence on forest resources, especially in the tropical forest of the Democratic Republic of Congo where the complexity of the relationship between local communities and their environment is still being studied.

The influence of stress on mental health among Chinese college students: The moderating role of psychological suzhi.

Depending on its duration, stress can be divided into chronic and acute stress, both of which can be detrimental to an individual's mental health. Psychological suzhi may act as a protective factor that buffers the adverse effects of stress. This study aimed to explore the moderating role of psychological suzhi in the relationship between these two types of stress and mental health based on a dual-factor model of mental health. Study 1 explored the moderating role of psychological suzhi on the relationship between chronic stress and mental health using the Adolescent Self-Rating Life Events Check List, College Student Psychological Suzhi Scale Brief Mental Health Version, Satisfaction With Life Scale, and 12-item General Health Questionnaire to investigate 919 Chinese college students. A hierarchical regression model was used to examine the moderating effects. Study 2 examined the moderating role of psychological suzhi on the relationship between acute stress and mental health. Participants (N = 56) were classified into high (N = 30) and low (N = 26) psychological suzhi groups based on the Psychological Suzhi Scale. They completed the Trier Social Stress Test for Groups and a specific control condition, and their state anxiety and happiness levels were assessed. Data were analyzed using a mixed-design repeated-measures ANOVA. The results of Study 1 revealed that psychological suzhi moderated the influence of chronic stress on the negative indicator of mental health (psychological symptoms) (ß = -0.18, t = -6.90, p < 0.001). The results of Study 2 showed that psychological suzhi moderated the effect of acute stress on the negative indicator of mental health (state anxiety) [F (1, 54) = 4.79, p < 0.05, η2 = 0.08]. Psychological suzhi can moderate the influence of both chronic and acute stress on the negative indicators of college students' mental health but cannot moderate the influence on the positive indicators of mental health.

Prevalence and influencing factors of post-traumatic stress disorder among Chinese healthcare workers during the COVID-19 epidemic: a systematic review and meta-analysis.

Background: Post-traumatic stress disorder is an important psychological problem affecting the physical mental health of Chinese healthcare workers during the COVID-19 pandemic. Aims: To estimate the prevalence and influencing factors of post-traumatic stress disorder (PTSD) among Chinese healthcare workers during COVID-19. Methods: Search of Chinese and English literature in PubMed, EMbase, Web of Science, Medline, Elsevier, SpringerLink, China Biomedical Literature Database, CNKI, Wan-fang, and CQVIP for the period from December 2019 to August 2023. Stata 14.0 software was used for data analysis. The methodological quality of each study was scored, and data were extracted from the published reports. Pooled prevalence was estimated using the Random-effects model. Publication bias was evaluated using Egger's test and Begg's test. Results: Twenty-one studies included 11841 Chinese healthcare workers in this review. First, the overall prevalence of Post-traumatic stress disorder among Chinese healthcare workers during the COVID-19 epidemic was 29.2% (95% CI: 20.7% to 33.7%). Twelve factors included in the meta-analysis were found to be protective against PTSD among Chinese healthcare workers: female, nurse, married, front-line work, less work experience, family or friend diagnosed with COVID-19, history of chronic disease and fear of COVID-19. Conversely, outside Hubei, higher education, social support and psychological resilience are protective factors. Conclusion: These recent findings increase our understanding of the psychological status of Chinese healthcare workers and encourage that long-term monitoring and long-term interventions should be implemented to improve the mental health of Chinese healthcare workers in the aftermath of the COVID-19.

Monomodular and multifunctional processive endocellulases: implications for swine nutrition and gut microbiome.

Poor efficiency of dietary fibre utilization not only limits global pork production profit margin but also adversely affects utilization of various dietary nutrients. Poor efficiency of dietary nutrient utilization further leads to excessive excretion of swine manure nutrients and results in environmental impacts of emission of major greenhouse gases (GHG), odor, nitrate leaching and surface-water eutrophication. Emission of the major GHG from intensive pork production contributes to global warming and deteriorates heat stress to pigs in tropical and sub-tropical swine production. Exogenous fibre enzymes of various microbial cellulases, hemicellulases and pectinases have been well studied and used in swine production as the non-nutritive gut modifier feed enzyme additives in the past over two decades. These research efforts have aimed to improve growth performance, nutrient utilization, intestinal fermentation as well as gut physiology, microbiome and health via complementing the porcine gut symbiotic microbial fibrolytic activities towards dietary fibre degradation. The widely reported exogenous fibre enzymes include the singular use of respective cellulases, hemicellulases and pectinases as well as their multienzyme cocktails. The currently applied exogenous fibre enzymes are largely limited by their inconsistent in vivo efficacy likely due to their less defined enzyme stability and limited biochemical property. More recently characterized monomodular, multifunctional and processive endoglucanases have the potential to be more efficaciously used as the next-generation designer fibre biocatalysts. These newly emerging multifunctional and processive endoglucanases have the potential to unleash dietary fibre sugar constituents as metabolic fuels and prebiotics, to optimize gut microbiome, to maintain gut permeability and to enhance performance in pigs under a challenged environment as well as to parallelly unlock biomass to manufacture biofuels and biomaterials.

Factors associated with prior completion of colorectal cancer and hepatitis C virus screenings among community health center patients: a cross-sectional study to inform a multi-behavioral educational intervention.

BACKGROUND: Colorectal cancer (CRC) and liver cancer are two of the leading causes of cancer death in the United States and persistent disparities in CRC and liver cancer incidence and outcomes exist. Chronic hepatitis C virus (HCV) infection is one of the main contributors to liver cancer. Effective screening for both CRC and HCV exist and are recommended for individuals based upon age, regardless of gender or sex assigned at birth. Recommendations for both screening behaviors have been recently updated. However, screening rates for both CRC and HCV are suboptimal. Targeting adoption of multiple screening behaviors has the potential to reduce cancer mortality and disparities. OBJECTIVE: To examine psychosocial factors associated with completion of CRC and HCV screenings in order to inform a multi-behavioral educational intervention that pairs CRC and HCV screening information. METHODS: A cross-sectional survey was conducted with participants (N = 50) recruited at two community health centers in Florida (United States). Kruskal-Wallis and Fisher's exact tests were used to examine associations between completion of both CRC and HCV screening, CRC and HCV knowledge, Preventive Health Model constructs (e.g., salience and coherence, response efficacy, social influence), and sociodemographic variables. RESULTS: Most participants were White (84%), female (56%), insured (80%), and reported a household income of $25,000 or less (53%). 30% reported ever previously completing both CRC and HCV screenings. Prior completion of both screening behaviors was associated with higher educational attainment (p = .014), having health insurance (p = .022), being U.S.-born (p = .043), and higher salience and coherence scores for CRC (p = .040) and HCV (p = .004). CONCLUSIONS: Findings demonstrate limited uptake of both CRC and HCV screenings among adults born between 1945 and 1965. Uptake was associated with multiple sociodemographic factors and health beliefs related to salience and coherence. Salience and coherence are modifiable factors associated with completion of both screening tests, suggesting the importance of incorporating these health beliefs in a multi-behavioral cancer education intervention. Additionally, health providers could simultaneously recommend and order CRC and HCV screening to improve uptake among this age cohort.

Safety outcomes of pembrolizumab with platinum agent chemotherapy combined with 5-fluorouracil or taxane derivative in head and neck cancer.

INTRODUCTION: For patients with metastatic head and neck squamous cell cancer (HNSCC), the outcomes of pembrolizumab in combination with a platinum agent and taxane as first-line therapy remain unknown. The purpose of this study is to characterize the impact of substituting the 5-fluorouracil (5-FU) backbone for a taxane in this chemoimmunotherapy regimen on safety/tolerability and survival outcomes. METHODS: This was an IRB-approved, single-center, retrospective, active comparator, new-user design study in adult patients with HNSCC treated between January 2018 and September 2021. The primary objective was to assess safety and tolerability of pembrolizumab in combination with a platinum agent and taxane against an active comparator arm of pembrolizumab in combination with a platinum agent and 5-FU. Safety and tolerability were evaluated by assessing differences in overall toxicities, with further secondary analysis evaluating differences in hematologic toxicities and pre-defined non-hematologic toxicities. RESULTS: There was no statistical difference demonstrated with the primary endpoint between the cohorts. Reduced toxicity rates were found in the taxane arm for mucositis and creatinine levels. No grade 4 non-hematologic toxicities were reported. Patients receiving 5-FU were more likely to have dose reductions upfront, discontinue treatment due to intolerances and had significantly higher mucositis. CONCLUSIONS: This study helps to characterize the safety profile and activity of pembrolizumab in combination with a platinum agent and taxane derivative in HNSCC patients. Within our study, substitution of 5-FU with a taxane did not show an increased risk of toxicities, worsened survival, or decreased odds of achieving a response. Mucositis and elevated creatinine rates were significantly reduced within the taxane arm.

Effectiveness of perioperative chemotherapy and radical cystectomy in treating bladder cancer.

BACKGROUND: Despite abundant evidence supporting the use of perioperative chemotherapy from clinical trials, no study to date has comprehensively evaluated its use in the treatment of muscle-invasive bladder cancer (MIBC) in the real-world setting. Little is known regarding the impact of pretreatment disease stage and real-world factors such as patient comorbidities preventing timely completion of therapy on its effectiveness. This study aims to assess the usage of perioperative chemotherapy and examines its impact on pathologic downstaging rates and recurrence free survival in patients undergoing radical cystectomy. METHODS: A retrospective review was conducted in 805 patients with muscle invasive bladder cancer undergoing radical cystectomy with no perioperative chemotherapy, 761 with presurgical chemotherapy followed by radical cystectomy, and 134 radical cystectomy followed by adjuvant chemotherapy. Relevant clinicopathologic features were reviewed. Recurrence-free survival and Overall Survival probability estimates were calculated using the Kaplan-Meier method and compared using the Log-rank or Gehan-Breslow tests. The prognostic effects of presurgical chemotherapy and adjuvant chemotherapy regimens were evaluated by estimating hazard ratio and 95% confidence interval from an adjusted Cox proportional hazards model. Statistical tests were 2-sided, and significance was defined as P-value < 0.05. RESULTS: In this contemporary, real-world cohort, 5-yr RFS was found to be 65.6% in pT0, 59.1%in pT2, and 10.8% in pN+ patients. Presurgical chemotherapy increased pathologic downstaging rates from 27.5% to 41.1% in patients with ≥cT2 BCa. Stratified by clinical T-stage, only cT2 patients derived recurrence-free survival (Median 45.3 months vs. 29.0 months, P < 0.01) and overall survival (Median 62.3 months vs. 41.9 months, P < 0.001) benefits.  In patients with adverse pathologic features (≥pT3 or pN+), adjuvant chemotherapy improved recurrence-free survival (Median 22.8 months vs. 10.0 months, P < 0.0001) and overall survival (Median OS 32.4 months vs. 16.3 months, P < 0.0001). CONCLUSIONS: We report real-world outcomes from a large cohort of muscle-invasive bladder cancer patients undergoing surgical treatment with/out perioperative chemotherapy. Pathologic response rates to pre-surgical chemotherapy were modest and led to clinical benefit only in cT2 patients. Adjuvant chemotherapy provided survival benefit for pathologically advanced MIBC patients irrespective of pT/N staging.

Collagen 1-mediated CXCL1 secretion in tumor cells activates fibroblasts to promote radioresistance of esophageal cancer.

Esophageal squamous-cell carcinoma (ESCC) is commonly treated with radiotherapy; however, radioresistance hinders its clinical effectiveness, and the underlying mechanism remains elusive. Here, we develop patient-derived xenografts (PDXs) from 19 patients with ESCC to investigate the mechanisms driving radioresistance. Using RNA sequencing, cytokine arrays, and single-cell RNA sequencing, we reveal an enrichment of cancer-associated fibroblast (CAF)-derived collagen type 1 (Col1) and tumor-cell-derived CXCL1 in non-responsive PDXs. Col1 not only promotes radioresistance by augmenting DNA repair capacity but also induces CXCL1 secretion in tumor cells. Additionally, CXCL1 further activates CAFs via the CXCR2-STAT3 pathway, establishing a positive feedback loop. Directly interfering with tumor-cell-derived CXCL1 or inhibiting the CXCL1-CXCR2 pathway effectively restores the radiosensitivity of radioresistant xenografts in vivo. Collectively, our study provides a comprehensive understanding of the molecular mechanisms underlying radioresistance and identifies potential targets to improve the efficacy of radiotherapy for ESCC.

Therapeutic effects of high-dose vitamin C supplementation in patients with COVID-19: a meta-analysis.

CONTEXT: Coronavirus disease 2019 (COVID-19) could induce the "cytokine storm" due to overactivation of immune system and accompanied by acute respiratory distress syndrome as a serious complication. Vitamin C has been effective in improving lung function of patients by reducing inflammation. OBJECTIVE: The aim was to explore the therapeutic effects of high-dose vitamin C supplementation for patients with COVID-19 using meta-analysis. DATA SOURCES: Published studies were searched from PubMed, Cochrane Library, Web of Science, EMBASE, and China National Knowledge Infrastructure databases up to August 2022 using the terms "vitamin C" and "COVID-19". Data analyses were performed independently by 2 researchers using the PRISMA guidelines. DATA EXTRACTION: Heterogeneity between the included studies was assessed using I2 statistics. When I2 ≥50%, the random-effects model was used; otherwise, a fixed-effects model was applied. Stata 14.0 software was used to pool data by standardized mean differences (SMDs) with 95% CIs or odds ratios (ORs) with 95% CIs. DATA ANALYSIS: The 14 studies had a total of 751 patients and 1583 control participants in 7 randomized controlled trials and 7 retrospective studies. The vitamin C supplement significantly increased ferritin (SMD = 0.272; 95% CI: 0.059 to 0.485; P = 0.012) and lymphocyte count levels (SMD = 0.376; 95% CI: 0.153 to 0.599; P = 0.001) in patients with COVID-19. Patients administered vitamin C in the length of intensive care unit staying (SMD = 0.226; 95% CI: 0.073 to 0.379; P = 0.004). Intake of vitamin C prominently alleviate disease aggravation (OR = 0.344, 95%CI: 0.135 to 0.873, P = 0.025). CONCLUSIONS: High-dose vitamin C supplementation can alleviate inflammatory response and hinder the aggravation of COVID-19.

Sociocultural factors associated with physical activity in Black prostate cancer survivors.

PURPOSE: Prostate cancer disproportionately affects Black men. Physical activity protects long-term health and quality of life outcomes in prostate cancer survivors. This study aimed to identify sociocultural factors related to physical activity among Black prostate cancer survivors to inform culturally tailored intervention development. METHODS: This secondary analysis included data from 257 men who identified as Black or African American and were diagnosed with prostate cancer between 2013 and 2018. Participants completed validated self-report measures of perceived history of racial discrimination, religiosity, fatalism, sociodemographic (e.g., age, ethnicity, income) and clinical characteristics (e.g., years since diagnosis, comorbidity burden), and leisure-time physical activity. Regression analyses were conducted to examine the associations between sociocultural factors and mild, moderate, and vigorous physical activity. RESULTS: Participants were on average 68.7 years old (SD = 7.7), and most were non-Hispanic (97.3%), married (68.9%), reported an annual household income above $50,000 (57.1%), received at least some college education (74.1%), and were overweight or had obesity (78.5%). Participants reported on average 88.1 (SD = 208.6) min of weekly mild physical activity, and most did not meet guidelines for weekly moderate (80.5%) or vigorous (73.0%) physical activity. After adjusting for covariates, older age and greater religiosity were associated with mild physical activity (ps ≤ 0.05). Higher levels of fatalism were associated with lower odds of meeting guidelines for moderate physical activity (OR = 0.87, 95% CI = 0.77-0.99). CONCLUSIONS: Sociocultural factors such as religiosity and fatalism may be associated with some forms of physical activity in Black prostate cancer survivors. These findings suggest that incorporating faith-based practices into health behavior interventions may be appropriate for this population.

The intratumor microbiome is associated with microsatellite instability.

Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden. Using whole transcriptome and whole genome sequencing microbial abundance data, we investigated associations of intratumoral microbes with MSI, survival, and MSI-relevant tumor molecular characteristics across multiple cancer types including colorectal cancer (CRC), stomach adenocarcinoma, and endometrial carcinoma. Among 451 CRC patients, our key finding was strong associations of multiple CRC-associated genera, including Dialister and Casatella, with MSI. Dialister and Casatella abundance was associated with improved overall survival (hazard ratiomortality = 0.56, 95% confidence interval = 0.34 to 0.92, and hazard ratiomortality = 0.44, 95% confidence interval = 0.27 to 0.72), respectively, comparing higher relative to lower quantiles. Multiple intratumor microbes were associated with immune genes and tumor mutational burden. Diversity of oral cavity-originating microbes was also associated with MSI among CRC and stomach adenocarcinoma patients. Overall, our findings suggest the intratumor microbiota may differ by MSI status and play a role in influencing the tumor microenvironment.

Spatial scale applicability of 4-Scale geometrical optics model canopy reflectance simulation.

Accurately clarifying the applicable spatial scale of 4-Scale model is conducive to improving the accuracy of its application in canopy reflectance simulation of different vegetation types, and to further improving the inversion accuracy of leaf area index, canopy density, and other parameters. Two forest plots (one for broad-leaved forest and one for mixed forest) with each area of 100 m×100 m in Maoershan Experimental Forest Farm, Shangzhi, Heilongjiang, were divided into the spatial scales of 10, 20, 30, 40 and 50 m, respectively. The 4-Scale model was used to simulate forest canopy reflectance. Local mean method, the nearest neighbor method, bilinear interpolation method, and cubic convolution method were used to convert Sentinel-2 images with spatial resolution of 10 m to other scales, with the results being evaluated. The simulated canopy reflectance and remote sensing pixel reflectance were compared and analyzed. The spatial scale of mixed forest and broad-leaved forest suitable for high-precision inversion parameters of 4-Scale model was determined. The results showed that the 4-Scale model underestimated the pixel forest canopy reflectance as a whole. The canopy reflectance of mixed forest and broad-leaved forest had the worst simulation effect at the 20 m scale. Both the root mean square error (RMSE) and the mean absolute error from (MAE) of red and near-infrared band were large. When the scale was >20 m, the simulation effect became better. The applicability of the model was the best when the mixed forest was 40 m and the broad-leaved forest was 30 m. The mean and standard deviation of the reflectance difference between the simulated value and the remote sensing pixel were the minimum in the red and near near-infrared bands, with the minimum RMSE and MAE. The simulation results of mixed forest and broad-leaved forest at 10 m scale were not stable, the rule of mean and standard deviation was inconsistent, and the difference between RMSE and MAE was large under the same band.

Epithelial cells activate fibroblasts to promote esophageal cancer development.

Esophageal squamous-cell carcinoma (ESCC) develops through multistage epithelial cancer formation, i.e., from normal epithelium, low- and high-grade intraepithelial neoplasia to invasive carcinoma. However, how the precancerous lesions progress to carcinoma remains elusive. Here, we report a comprehensive single-cell RNA sequencing and spatial transcriptomic study of 79 multistage esophageal lesions from 29 patients with ESCC. We reveal a gradual and significant loss of ANXA1 expression in epithelial cells due to its transcription factor KLF4 suppression along the lesion progression. We demonstrate that ANXA1 is a ligand to formyl peptide receptor type 2 (FPR2) on fibroblasts that maintain fibroblast homeostasis. Loss of ANXA1 leads to uncontrolled transformation of normal fibroblasts into cancer-associated fibroblasts (CAFs), which can be enhanced by secreted TGF-ß from malignant epithelial cells. Given the role of CAFs in cancer, our study underscores ANXA1/FPR2 signaling as an important crosstalk mechanism between epithelial cells and fibroblasts in promoting ESCC.

Delineation of clinical course, outcomes, and prognostic factors in patients with T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare, post-thymic T-cell neoplasm with a diverse clinical course. T-PLL is typically associated with a poor prognosis; however, a subset of patients have inactive disease on initial presentation. There is a lack of accurate delineation of the disease based on initial clinical presentation and pathological assessment, hindering clinical decision-making. To characterize and delineate disease subtypes based on initial clinical presentation and pathologic assessment, we retrospectively reviewed 81 patients with T-PLL treated at our institution. We compared patients with T-PLL who initially presented with a relatively indolent or stable disease course to those with an aggressive disease course. Clinicopathologic characteristics, overall survival (OS), and prognostic factors were analyzed. Patients with inactive disease had a significantly longer OS than patients with active disease. At diagnosis, presence of B symptoms, low hemoglobin, low platelet count, lymphocyte doubling time of fewer than 3 months, and abnormal cytogenetics were associated with shorter OS. Cell morphology, immunophenotype, absolute lymphocyte count, lactate dehydrogenase levels, involvement of liver, spleen, skin or central nervous system, presence of TCL1 rearrangement or inv (14)/t(14;14), presence of chromosome 8 abnormalities, and presence of deletion of 11q were not associated with significant OS difference among the patients. Receiving alemtuzumab as first-line treatment and consolidation with allogeneic hematopoietic stem cell transplant were associated with better outcomes. T-PLL inactive and active disease subtypes can exhibit overlapping yet different clinical and pathological features. We describe several prognostic factors at diagnosis that can be used for risk stratification and aid in guiding treatment decisions.

Patient-caregiver dyads in pancreatic cancer: identification of patient and caregiver factors associated with caregiver well-being.

We aimed to examine the psychosocial well-being in the pancreas cancer patient-caregiver dyad, and determine patient and caregiver characteristics that predict caregiver distress. This was a cross-sectional, observational study. Demographics and caregiving characteristics were gathered from patients and caregivers. Caregivers completed validated instruments investigating anxiety, depression, perceived stress and caregiver burden. Over a period of eleven months, 128 patient-caregiver dyads were enrolled. Patient and caregiver distress scores were not associated with patient clinical disease burden. Patient distress was a significant predictor of concurrent caregiver distress, anxiety, depression, and perceived burden. Younger caregivers were also associated with higher caregiver anxiety and perceived burden. Additionally, number of caregiving activities and caregiver overall health status were predictors of concurrent caregiver depression and perceived stress. Certain pancreatic cancer patient and caregiver variables may negatively impact the well-being of caregivers. Future efforts should focus on development and implementation of comprehensive caregiver support programs for those at risk for psychosocial distress.

Prognostic and Predictive Value of PIK3CA Mutations in Metastatic Colorectal Cancer.

BACKGROUND: Comprehensive genomic profiling is used to guide the management of metastatic colorectal cancer (mCRC); however, the role of PIK3CA mutations, present in up to 20% of mCRCs, is unclear. OBJECTIVE: This study aimed to evaluate the association of PIK3CA mutations with other common mutations in mCRC and determine the prognostic and predictive value of PIK3CA mutations. PATIENTS AND METHODS: A retrospective chart review was performed on patients in the Moffitt Clinical Genomic Database with mCRC. A meta-analysis was performed to further evaluate the predictive value of PIK3CA mutations to the response to anti-epidermal growth factor receptor (EGFR) therapy. RESULTS: Among 639 patients, PIK3CA was positively correlated with KRAS mutation (r = 0.11, p = 0.006) and negatively correlated with TP53 mutation (r = - 0.18, p ≤ 0.001) and ERBB2 amplification (r = - 0.08, p = 0.046). The median overall survival (OS) of patients with PIK3CA-mutant mCRC (n = 49) was 35.5 (95% confidence interval [CI] 18.7-48.1) months vs. 55.3 (95% CI 47.5-65.6) months for PIK3CA wild-type mCRC (n = 286) [p = 0.003]. This OS difference remained significant with exon 9 and exon 20 subset analyses. There was no significant difference in response rate between patients with PIK3CA wild-type (n = 97) versus mutant (n = 9) mCRC who received anti-EGFR therapy (43% vs. 56%, p = 0.61) and no significant difference in median progression-free survival (PFS) of 10.3 versus 7.2 months (p = 0.60). However, our meta-analysis of 12 studies, including ours, using a common effect model identified that PIK3CA mutations are associated with reduced response to anti-EGFR therapy, with a relative risk of 0.56 (95% CI 0.38-0.82). CONCLUSION: Our study identified PIK3CA mutations as a poor prognostic factor, and our meta-analysis identified PIK3CA mutations as predictive of decreased response to anti-EGFR therapy in patients with mCRC.

Computational Identification of Preneoplastic Cells Displaying High Stemness and Risk of Cancer Progression.

Evidence points toward the differentiation state of cells as a marker of cancer risk and progression. Measuring the differentiation state of single cells in a preneoplastic population could thus enable novel strategies for early detection and risk prediction. Recent maps of somatic mutagenesis in normal tissues from young healthy individuals have revealed cancer driver mutations, indicating that these do not correlate well with differentiation state and that other molecular events also contribute to cancer development. We hypothesized that the differentiation state of single cells can be measured by estimating the regulatory activity of the transcription factors (TF) that control differentiation within that cell lineage. To this end, we present a novel computational method called CancerStemID that estimates a stemness index of cells from single-cell RNA sequencing data. CancerStemID is validated in two human esophageal squamous cell carcinoma (ESCC) cohorts, demonstrating how it can identify undifferentiated preneoplastic cells whose transcriptomic state is overrepresented in invasive cancer. Spatial transcriptomics and whole-genome bisulfite sequencing demonstrated that differentiation activity of tissue-specific TFs was decreased in cancer cells compared with the basal cell-of-origin layer and established that differentiation state correlated with differential DNA methylation at the promoters of these TFs, independently of underlying NOTCH1 and TP53 mutations. The findings were replicated in a mouse model of ESCC development, and the broad applicability of CancerStemID to other cancer-types was demonstrated. In summary, these data support an epigenetic stem-cell model of oncogenesis and highlight a novel computational strategy to identify stem-like preneoplastic cells that undergo positive selection. SIGNIFICANCE: This study develops a computational strategy to dissect the heterogeneity of differentiation states within a preneoplastic cell population, allowing identification of stem-like cells that may drive cancer progression.

Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma.

This study investigates aberrant DNA methylations as potential diagnosis and prognosis markers for esophageal squamous-cell carcinoma (ESCC), which if diagnosed at advanced stages has <30% five-year survival rate. Comparing genome-wide methylation sites of 91 ESCC and matched adjacent normal tissues, we identified 35,577 differentially methylated CpG sites (DMCs) and characterized their distribution patterns. Integrating whole-genome DNA and RNA-sequencing data of the same samples, we found multiple dysregulated transcription factors and ESCC-specific genomic correlates of identified DMCs. Using featured DMCs, we developed a 12-marker diagnostic panel with high accuracy in our dataset and the TCGA ESCC dataset, and a 4-marker prognostic panel distinguishing high-risk patients. In-vitro experiments validated the functions of 4 marker host genes. Together these results provide additional evidence for the important roles of aberrant DNA methylations in ESCC development and progression. Our DMC-based diagnostic and prognostic panels have potential values for clinical care of ESCC, laying foundations for developing targeted methylation assays for future non-invasive cancer detection methods.