Rationale, Procedures, and Response Rates for a Pilot Study to Sample Cancer Survivors for NCI's Health Information National Trends Survey: HINTS-SEER 2021.

The National Cancer Institute's (NCI) Health Information National Trends Survey (HINTS) is a nationally representative survey of U.S. adults in which 12-17% of respondents report a cancer history. To increase representation from adult cancer survivors, in 2021, NCI sampled survivors from three Surveillance, Epidemiology, and End Results (SEER) program cancer registries: Iowa, New Mexico, and the Greater Bay Area. Sampling frames were stratified by time since diagnosis and race/ethnicity, with nonmalignant tumors and non-melanoma skin cancers excluded. Participants completed a self-administered postal questionnaire. The overall response rate for HINTS-SEER (N = 1,234) was 12.6%; a non-response bias analysis indicated few demographic differences between respondents and the pool of sampled patients in each registry. Most of the sample was 10+ years since diagnosis (n = 722; 60.2%); 392 respondents were 5 to < 10 years since diagnosis (29.6%); and 120 were < 5 years since diagnosis (10.2%). Common cancers included male reproductive (n = 304; 24.6%), female breast (n = 284; 23.0%), melanoma (n = 119; 9.6%), and gastrointestinal (n = 106; 8.6%). Tumors were mostly localized (67.8%; n = 833), with 22.4% (n = 282) regional, 6.2% (n = 72) distant, and 3.7% (n = 47) unknown. HINTS-SEER data are available by request and may be used for secondary analyses to examine a range of social, behavioral, and healthcare outcomes among cancer survivors.

Divergent dynamics: disasters and conflicts as 'drivers' of internal displacement?

Disasters and conflicts are both widely recognised as 'drivers' of internal displacement. Yet, despite a growing body of research and policy, there has been little consideration to date of how the different features of each 'context' shape the micro-level dynamics of internal displacement. Where and why are these dynamics similar across the two contexts and how do they differ? This paper draws on general concepts from the disaster field to develop a comparative analytical model of internal displacement dynamics in the disaster and conflict contexts. Based on inferences from the patchy extant data across the two contexts, it identifies and explains points of convergence and divergence between internal displacement dynamics in both the disaster and conflict contexts. This 'contextual' model of the micro-level dynamics of internal displacement has implications for academic debates, as well as for policy and practice, in the disaster, conflict, peace, climate change, and forced migration/displacement fields.

Three-dimensional compaction of soft granular packings.

This paper analyzes the compaction behavior of assemblies composed of soft (elastic) spherical particles beyond the jammed state, using three-dimensional non-smooth contact dynamic simulations. The assemblies of particles are characterized using the evolution of the packing fraction, the coordination number, and the von Misses stress distribution within the particles as the confining stress increases. The packing fraction increases and tends toward a maximum value close to 1, and the mean coordination number increases as a square root of the packing fraction. As the confining stress increases, a transition is observed from a granular-like material with exponential tails of the shear stress distributions to a continuous-like material characterized by Gaussian-like distributions of the shear stresses. We develop an equation that describes the evolution of the packing fraction as a function of the applied pressure. This equation, based on the micromechanical expression of the granular stress tensor, the limit of the Hertz contact law for small deformation, and the power-law relation between the packing fraction and the coordination of the particles, provides good predictions from the jamming point up to very high densities without the need for tuning any parameters.

Proteomic investigations into resistance in colorectal cancer.

Introduction: Despite advances in screening and treatment options, colorectal cancer (CRC) remains one of the most prevalent and lethal cancer subtypes. Resistance to cytotoxic or targeted therapy has remained a constant challenge to the treatment and long-term management of patients, attracting intense worldwide investigation since the 1950s. Through extensive investigations into the proteomic mechanisms and functions that convey resistance to therapy/s, researchers have become able to implicate alterations in several signaling pathways that provide and sustain resistance to treatment.Areas covered: In this review, we summarize how protein alterations are associated with resistance to therapy, with particular emphasis on CRC. An overview of the mechanisms of therapeutic resistance is described, highlighting recent studies which endeavor to elucidate the proteomic changes that are associated with the acquisition and promulgation of therapeutic resistance.Expert opinion: While cancers such as CRC have been intensively studied for decades, unresponsiveness and the resistance to therapy remain critical obstacles in the treatment of patients. Due to the inherent biological and clinical heterogeneity of individual CRCs, proteomic methods stand to become powerful tools to provide biological insights that may guide therapeutic strategies with the ultimate goal of refining emergent immunotherapeutic treatments.

Compaction Model for Highly Deformable Particle Assemblies.

The compaction behavior of deformable grain assemblies beyond jamming remains bewildering, and existing models that seek to find the relationship between the confining pressure P and solid fraction ϕ end up settling for empirical strategies or fitting parameters. Using a coupled discrete-finite element method, we analyze assemblies of highly deformable frictional grains under compression. We show that the solid fraction evolves nonlinearly from the jamming point and asymptotically tends to unity. Based on the micromechanical definition of the granular stress tensor, we develop a theoretical model, free from ad hoc parameters, correctly mapping the evolution of ϕ with P. Our approach unveils the fundamental features of the compaction process arising from the joint evolution of grain connectivity and the behavior of single representative grains. This theoretical framework also allows us to deduce a bulk modulus equation showing an excellent agreement with our numerical data.

The chromatin-associated Sin3B protein is required for hematopoietic stem cell functions in mice.

Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy and are the origin of all blood cells produced throughout an individual's life. The balance between HSC self-renewal and differentiation is maintained by various intrinsic and extrinsic mechanisms. Among these, the molecular pathways that restrict cell cycle progression are critical to the maintenance of functional HSCs. Alterations in the regulation of cell cycle progression in HSCs invariably lead to the development of hematologic malignancies or bone marrow failure syndromes. Here we report that hematopoietic-specific genetic inactivation of Sin3B, an essential component of the mammalian Sin3-histone deacetylase corepressor complex, severely impairs the competitive repopulation capacity of HSCs. Sin3B-deleted HSCs accumulate and fail to properly differentiate following transplantation. Moreover, Sin3B inactivation impairs HSC quiescence and sensitizes mice to myelosuppressive therapy. Together, these results identify Sin3B as a novel and critical regulator of HSC functions.

The Effect of Fixation Technique on Continuous Interscalene Nerve Block Catheter Success: A Randomized, Double-Blind Trial.

BACKGROUND: Continuous peripheral nerve blocks offer advantages over single-injection blocks, including extended analgesia and reduction in opioid consumption. These benefits require that the perineural catheter remain intact for the duration of the planned local anesthetic infusion. Mechanical displacement of catheters, leaking, and consequent failure are known complications. The aim of this study was to evaluate continuous perineural catheter tip-to-nerve apposition in vivo over 48 hours comparing 2 different simple fixation strategies. METHODS: Subjects presenting for a continuous interscalene nerve block were randomized to perineural catheter fixation with 1 of 2 types of adhesive: Dermabond (2-octylcyanoacrylate) or Mastisol (alcohol 23A, gum mastic, storax, and methyl salicylate), covered with a simple transparent dressing. The primary outcome was the evaluation of catheter-to-nerve apposition maintenance over 48 hours via both a blinded ultrasound evaluation of local anesthetic distribution and a blinded clinical assessment. Secondary outcomes included leakage at the catheter site, pain scores, opioid consumption, catheter-to-skin migration at the insertion site, and patient satisfaction. RESULTS: Sixty-six subjects were recruited and randomized to compare adhesive group catheter tip-to-nerve apposition on postoperative day 2 (POD 2). Within the intention-to-treat cohort, a statistically significant decrease of perineural catheter tip-to-nerve apposition in the Mastisol group (64.7%) compared with the Dermabond group (90.6%) on POD 2 (odds ratios [OR] 0.19; 95% confidence interval [CI] 0.05-0.75; P = .012) was observed. Similar results were observed on POD 1 (OR 0.19; 95% CI 0.03-1.38; P = NS) and POD 2 (OR 0.14; 95% CI 0.02-0.97; P = .008) within the as-treated cohort. Catheter leakage (OR 67; 95% CI 7.3-589) and median catheter migration difference at the skin insertion site (2.0 cm; 95% CI 0.5-2.5) were also significantly greater in the Mastisol group than in the Dermabond group from POD 0 to POD 2 (P < .001). Median postoperative opioid consumption difference in morphine equivalents (3.2 mg; 95% CI - 9.0 to 14.2) was not significantly different between the Dermabond and the Mastisol groups through POD 2 (P = .542). CONCLUSIONS: Perineural catheter fixation with Dermabond in continuous interscalene nerve block improves maintenance of catheter-to-nerve apposition when compared with Mastisol.

A Nonresponse Bias Analysis of the Health Information National Trends Survey (HINTS).

We conducted a nonresponse bias analysis of the Health Information National Trends Survey (HINTS) 4, Cycles 1 and 3, collected in 2011 and 2013, respectively, using three analysis methods: comparison of response rates for subgroups, comparison of estimates with weighting adjustments and external benchmarks, and level-of-effort analysis. Areas with higher concentrations of low socioeconomic status, higher concentrations of young households, and higher concentrations of minority and Hispanic populations had lower response rates. Estimates of health information seeking behavior were higher in HINTS compared to the National Health Interview Survey (NHIS). The HINTS estimate of doctors always explaining things in a way that the patient understands was not significantly different from the same estimate from the Medical Expenditure Panel Survey (MEPS); however, the HINTS estimate of health professionals always spending enough time with the patient was significantly lower than the same estimate from MEPS. A level-of-effort analysis found that those who respond later in the survey field period were less likely to have looked for information about health in the past 12 months, but found only small differences between early and late respondents for the majority of estimates examined. There is some evidence that estimates from HINTS could be biased toward finding higher levels of health information seeking.

Rationale, Procedures, and Response Rates for the 2015 Administration of NCI's Health Information National Trends Survey: HINTS-FDA 2015.

The National Cancer Institute (NCI) developed the Health Information National Trends Survey (HINTS) to monitor population trends in cancer communication practices, information preferences, health risk behaviors, attitudes, and cancer knowledge. The U.S. Food and Drug Administration (FDA) recognized HINTS as a unique data resource for informing its health communication endeavors and partnered with NCI to field HINTS-FDA 2015. HINTS-FDA 2015 was a self-administered paper instrument sent by mail May 29 to September 8, 2015, using a random probability-based sample of U.S. postal addresses stratified by county-level smoking rates, with an oversampling of high and medium-high smoking strata to increase the yield of current smokers responding to the survey. The response rate for HINTS-FDA 2015 was 33% (N = 3,738). The yield of current smokers (n = 495) was lower than expected, but the sampling strategy achieved the goal of obtaining more former smokers (n = 1,132). Public-use HINTS-FDA 2015 data and supporting documentation have been available for download and secondary data analyses since June 2016 at http://hints.cancer.gov . NCI and FDA encourage the use of HINTS-FDA for health communication research and practice related to tobacco-related communications, public knowledge, and behaviors as well as beliefs and actions related to medical products and dietary supplements.

Recent findings from the Human Proteome Project: opening the mass spectrometry toolbox to advance cancer diagnosis, surveillance and treatment.

The Human Proteome Project stands to eclipse the Human Genome Project in terms of scope, content and interpretation. Its outputs, in conjunction with recent developments across the proteomics community, provide new tools for cancer research with the potential of providing clinically relevant insights into the disease. These collectively may guide the development of future diagnosis, surveillance and treatment strategies. Having established a robust organizational framework within the international community, the Human Proteome Organization and the proteomics community at large have made significant advances in biomarker discovery, detection, molecular imaging and in exploring tumor heterogeneity. Here, the authors discuss some developments in cancer proteomics and how they can be implemented to reduce the global burden of the disease.

A novel multiplexed immunoassay identifies CEA, IL-8 and prolactin as prospective markers for Dukes' stages A-D colorectal cancers.

BACKGROUND: Current methods widely deployed for colorectal cancers (CRC) screening lack the necessary sensitivity and specificity required for population-based early disease detection. Cancer-specific protein biomarkers are thought to be produced either by the tumor itself or other tissues in response to the presence of cancers or associated conditions. Equally, known examples of cancer protein biomarkers (e.g., PSA, CA125, CA19-9, CEA, AFP) are frequently found in plasma at very low concentration (pg/mL-ng/mL). New sensitive and specific assays are therefore urgently required to detect the disease at an early stage when prognosis is good following surgical resection. This study was designed to meet the longstanding unmet clinical need for earlier CRC detection by measuring plasma candidate biomarkers of cancer onset and progression in a clinical stage-specific manner. EDTA plasma samples (1 µL) obtained from 75 patients with Dukes' staged CRC or unaffected controls (age and sex matched with stringent inclusion/exclusion criteria) were assayed for expression of 92 human proteins employing the Proseek® Multiplex Oncology I proximity extension assay. An identical set of plasma samples were analyzed utilizing the Bio-Plex Pro™ human cytokine 27-plex immunoassay. RESULTS: Similar quantitative expression patterns for 13 plasma antigens common to both platforms endorsed the potential efficacy of Proseek as an immune-based multiplex assay for proteomic biomarker research. Proseek found that expression of Carcinoembryonic Antigen (CEA), IL-8 and prolactin are significantly correlated with CRC stage. CONCLUSIONS: CEA, IL-8 and prolactin expression were found to identify between control (unaffected), non-malignant (Dukes' A + B) and malignant (Dukes' C + D) stages.

Facility-based active management of the third stage of labour: assessment of quality in six countries in sub-Saharan Africa.

OBJECTIVE: To assess the quality of facility-based active management of the third stage of labour in Ethiopia, Kenya, Madagascar, Mozambique, Rwanda and the United Republic of Tanzania. METHODS: Between 2009 and 2012, using a cross-sectional design, 2317 women in 390 health facilities were directly observed during the third stage of labour. Observers recorded the use of uterotonic medicines, controlled cord traction and uterine massage. Facility infrastructure and supplies needed for active management were audited and relevant guidelines reviewed. FINDINGS: Most (94%; 2173) of the women observed were given oxytocin (2043) or another uterotonic (130). The frequencies of controlled cord traction and uterine massage and the timing of uterotonic administration showed considerable between-country variation. Of the women given a uterotonic, 1640 (76%) received it within three minutes of the birth. Uterotonics and related supplies were generally available onsite. Although all of the study countries had national policies and/or guidelines that supported the active management of the third stage of labour, the presence of guidelines in facilities varied across countries and only 377 (36%) of 1037 investigated providers had received relevant training in the previous three years. CONCLUSION: In the study countries, quality and coverage of the active management of the third stage of labour were high. However, to improve active management, there needs to be more research on optimizing the timing of uterotonic administration. Training on the use of new clinical guidelines and implementation research on the best methods to update such training are also needed.

Characterization of the interaction between heterodimeric αvß6 integrin and urokinase plasminogen activator receptor (uPAR) using functional proteomics.

Urokinase plasminogen activator receptor (uPAR) and the epithelial integrin αvß6 are thought to individually play critical roles in cancer metastasis. These observations have been highlighted by the recent discovery (by proteomics) of an interaction between these two molecules, which are also both implicated in the epithelial-mesenchymal transition (EMT) that facilitates escape of cells from tissue barriers and is a common signature of cancer metastases. In this study, orthogonal in cellulo and in vitro functional proteomic approaches were used to better characterize the uPAR·αvß6 interaction. Proximity ligation assays (PLA) confirmed the uPAR·αvß6 interaction on OVCA429 (ovarian cancer line) and four different colon cancer cell lines including positive controls in cells with de novo ß6 subunit expression. PLA studies were then validated using peptide arrays, which also identified potential physical sites of uPAR interaction with αvß6, as well as verifying interactions with other known uPAR ligands (e.g., uPA, vitronectin) and individual integrin subunits (i.e., αv, ß1, ß3, and ß6 alone). Our data suggest that interaction with uPAR requires expression of the complete αß heterodimer (e.g., αvß6), not individual subunits (i.e., αv, ß1, ß3, or ß6). Finally, using in silico structural analyses in concert with these functional proteomics studies, we propose and demonstrate that the most likely unique sites of interaction between αvß6 and uPAR are located in uPAR domains II and III.

Brief Report: Long-Term Follow-Up of Adjuvant Pembrolizumab After Locally Ablative Therapy for Oligometastatic NSCLC.

Introduction: Patients with oligometastatic NSCLC benefit from locally ablative therapies (LAT); the role of adjuvant systemic therapies, however, remains less clear. In a single-arm, phase II clinical trial, we found that patients with oligometastatic NSCLC treated with a year of pembrolizumab after LAT had superior progression-free survival (PFS) compared with a historical control cohort. Herein, we present long-term follow-up on PFS and overall survival (OS). Methods: From February 1, 2015, to September 30, 2017, 45 patients with synchronous or metachronous oligometastatic (≤4 metastatic sites) NSCLC treated with LAT to all sites received adjuvant pembrolizumab every 21 days for up to 16 cycles. The primary efficacy end point was PFS from the start of pembrolizumab. Secondary end points included OS and safety. Median duration of follow-up was 66 months, and data cutoff was December 1, 2022. Results: A total of 45 patients were enrolled and treated with pembrolizumab after LAT (median age, 64 y [range, 46-82]; 21 women [47%]; 31 with a solitary oligometastatic site [69%]). At the data cutoff, 32 patients had progressive disease, 19 patients had died, and 13 patients had no evidence of relapse. Median PFS was 19.7 months (95% confidence interval: 7.6-31.7 mo); median OS was not reached (95% confidence interval: 37.7 mo-not reached). OS at 5 years was 60.0% (SE, 7.4%). Metachronous oligometastatic disease was associated with improved OS and PFS through Cox proportional hazard models. Conclusions: Pembrolizumab after LAT for oligometastatic NSCLC results in promising PFS and OS with a tolerable safety profile.

Transgenic, high-protein sorghums display promise in poultry diets in an initial comparison.

This study aimed to compare the inclusion of transgenic sorghums against commercially available sorghums on growth performance in broiler chickens. Isonitrogenous and isoenergetic diets were offered to a total 288 male Ross 308 broiler chickens from 14 to 35 d posthatch. Three dietary treatments were diets based on transgenic sorghums with a mean protein content of 154.7 g/kg and 5 treatments were based on commercially available sorghum hybrids with a mean protein content of 90.6 g/kg. Soybean meal inclusions in the commercial sorghum diets averaged 215 g/kg, which was reduced to 171 g/kg in the transgenic sorghum diets because of the higher protein contents. Overall growth performance was highly satisfactory, and commercial sorghums supported 2.55% (2,330 vs. 2,272 g/bird; P = 0.010) more weight gains and 2.74% (2,929 vs. 2,851 g/bird; P = 0.012) higher feed intakes; however, the transgenic sorghums supported a fractionally better FCR (1.255 vs 1.257; P = 0.826). There were no statistical differences in apparent jejunal and ileal starch and protein (N) digestibility coefficients between treatments. The transgenic sorghum diets generated slightly, but significantly, higher AME:GE ratios and AMEn, but the commercial sorghum diets generated 6.33% (235 vs. 221 g/kg; P < 0.001) greater breast meat yields. Apparent ileal digestibility coefficients of 16 amino acids averaged 0.839 and 0.832 for transgenic and commercial sorghum-based diets, respectively, without any significant differences in individual amino acids. This outcome suggests amino acid digestibilities of the transgenic sorghums may be inherently higher than commercial hybrid sorghums as the 25.7% higher average soybean meal inclusions would have advantaged amino acid digestibilities in commercial sorghum diets. The possibility that the digestibilities of amino acids in the kafirin component of transgenic sorghums was enhanced by modifications to the structure of kafirin protein bodies is discussed. In conclusion, transgenic sorghums with higher protein concentrations led to 20.5% reduction of soybean meal inclusions in broiler diets, and this change did not compromise feed conversion efficiency compared to standard commercial hybrid sorghums.

Overexpression of αvß6 integrin alters the colorectal cancer cell proteome in favor of elevated proliferation and a switching in cellular adhesion that increases invasion.

Many proteins enhance cancer progression toward life-threatening metastases. These include linking proteins called integrins that mediate cell adhesion to the extracellular matrix (ECM), consequently altering both function and phenotype. Specific neoexpression of the ß6 integrin subunit correlates with the epithelial-to-mesenchymal transition, metastasis, and poor overall patient survival. While ß6 is implicated in these processes, exactly how it affects signaling and/or proteolytic pathways in metastasis remains unclear. A membrane-enriched peptide immobilized pH gradient isoelectric focusing (IPG-IEF) shotgun proteomics study was undertaken in which subclones of the SW480 colorectal cancer cell line transfected with a vector inducing unregulated ß6 integrin overexpression were compared with the "empty" mock vector control cell line. ß6 overexpression induced a significant change in 708 proteins and was found to be localized across most intracellular locations, some involving cellular processes and pathways underpinning cancer progression. Proteomics data have been deposited to the ProteomeXchange with identifier PXD000230. ß6 expression increased cell proliferation 4-fold while decreasing cell adhesion to many integrin ECM substrates. ß6 expression also enhanced cell invasion and promoted the expression/repression of many established cancer-related pathways.

Chromosome 7-centric analysis of proteomics data from a panel of human colon carcinoma cell lines.

In this manuscript, we describe a shotgun proteomics approach for a comprehensive proteomic analysis of samples including total lysates, membrane, secretome, and exosome fractions from a panel of colorectal cancer cell lines. We will present an analysis of our proteomics data in two alternative formats. First we will discuss a traditional analysis of our data, in which we identify a number of cancer-associated proteins using various proteomic data analysis tools. In a second approach, we use a chromosome format to organize the proteomic data on chromosome 7, allowing the identification of clusters of cancer-associated genes with boundaries defined by physical proximity on different chromosomes.

Targeting KRAS-Mutated NSCLC: Novel TKIs and Beyond.

KRAS-mutated non-small cell lung cancer (NSCLC) is the most common genetically altered subtype of NSCLC, yet targeted therapies remain limited. Multiple studies have investigated combinations of MEK inhibitors with chemotherapy without success. Here we discuss these studies and novel approaches to targeting KRAS-mutated NSCLC. See related article by Gadgeel et al., p. 3641.

Analysis of health overseas development aid for internally displaced persons in low- and middle-income countries.

Background: There are an estimated 55 million internally displaced persons (IDPs) globally. IDPs commonly have worse health outcomes than host populations and other forcibly displaced populations such as refugees. Official development assistance (ODA) is a major source of the global financial response for health in low- and middle-income countries (LMICs), including for populations affected by armed conflict and forced displacement. Analysis of ODA supports efforts to improve donor accountability, transparency and the equitable use of ODA. The aim of this study is to examine international donor support and responsiveness to IDP health needs through analysis of ODA disbursements to LMICs between 2010 and 2019. Methods: ODA disbursement data to LMICs from 2010 to 2019 were extracted from the Creditor Reporting System (CRS) database and analysed with Stata software using a combination of: (i) text searching for IDP and refugee related terms; and (ii) relevant health and humanitarian CRS purpose codes. Descriptive analysis was used to examine patterns of ODA disbursement, and nonlinear least squared regression analysis was used to examine responsiveness of ODA disbursement to recipient country IDP population size and health system capacity and health characteristics. Findings: The study highlighted declining per IDP capita health ODA from USD 5.34 in 2010 to USD 3.72 in 2019 (with annual average decline of -38% from the 2010 baseline). In contrast, health ODA for refugees in LMICs increased from USD 18.55 in 2010 to USD 23.31 in 2019 (with an annual average increase of +14%). Certain health topics for IDPs received very low ODA, with only 0.44% of IDP health ODA disbursed for non-communicable diseases (including mental health). There was also weak evidence of IDP health ODA being related to recipient country IDP population size, and health system capacity and health characteristics. The paper highlights the need for increased investment by donors in IDP health ODA and to ensure that it is responsive to their health needs.