Molecular basis for the interactions of eIF2ß with eIF5, eIF2B, and 5MP1 and their regulation by CK2.

The heterotrimeric GTPase eukaryotic translation initiation factor 2 (eIF2) delivers the initiator Met-tRNAi to the ribosomal translation preinitiation complex. eIF2ß has three lysine-rich repeats (K-boxes) in its N-terminal tail, which are important for binding to the GTPase-activating protein (GAP) eIF5, the guanine nucleotide exchange factor (GEF) eIF2B, and the regulator eIF5-mimic protein (5MP). Here, we combine X-ray crystallography with NMR to understand the molecular basis and dynamics of these interactions. The crystal structure of yeast eIF5-CTD in complex with K-box 3 of eIF2ß reveals an extended binding site on eIF2ß, far beyond the K-box. We show that human eIF5, eIF2Bε, and 5MP1 can all bind to each of the three K-boxes, while reducing each other's affinities. Moreover, all these affinities are increased by CK2 phosphomimetic mutations. Our results reveal how eIF5, eIF2B, and 5MP displace each other from eIF2, and elucidate the role of CK2 in remodeling the translation apparatus.

Examining characteristics and sampling methods of phosphor dynamics in lowland catchments.

Despite over two decades since the EU Water Framework Directive have passed, achieving the desired water quality in German surface waters remains challenging, regardless of efforts to reduce phosphorus inputs and associated environmental impacts. This study aims at analyzing the characteristics governing the concentrations of four key water quality parameters (total phosphorus, orthophosphate, particulate phosphate, and suspended solids) in two lowland catchments: the 50 km2 catchment of the Kielstau, Germany, and its 7 km2 tributary, the Moorau, which are dominated by agricultural land use. To this end, different sampling methods, particularly high-resolution precipitation event-based sampling and daily mixed samples, are conducted and evaluated, and their effectiveness is compared. The identification of sources and characteristics that affect phosphorus and suspended sediment dynamics, both in general and specifically during heavy precipitation events, is one focus of the study. Over a 15-year period, increasing concentrations of these parameters were observed in daily mixed samples, exhibiting distinct seasonal patterns-higher in summer and lower in winter-consistent with lowland catchment behavior. Particularly during heavy precipitation events, the smaller catchment exhibits a more complex and less predictable response to chemical concentrations compared with the dilution effect observed in the larger catchment. The results underline the complexity of phosphorus dynamics in small catchments and emphasize the importance of event-based sampling for capturing short-term concentration peaks for all four parameters, particularly beneficial regarding measuring suspended solids. While daily mixed samples capture average phosphorus concentrations, event-based sampling is crucial for detecting short-term spikes, providing a more comprehensive understanding of phosphorus dynamics.

Spatial expression of claudin 18.2 in matched primaries and metastases of tubo-ovarian carcinoma of all subtypes.

Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases.Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining.Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype.In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes.

BACKGROUND: Grading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. OBJECTIVE: To develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. DESIGN, SETTING, AND PARTICIPANTS: Tissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: GGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. RESULTS AND LIMITATIONS: Integration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. CONCLUSIONS: We propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. PATIENT SUMMARY: We developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.

PreCancer Atlas: Present and Future.

Precancer atlases have the potential to revolutionize how we think about the topographic and morphologic structures of precancerous lesions in relation to cellular, molecular, genetic, and pathophysiologic states. This mini review uses the Human Tumor Atlas Network (HTAN), established by the National Cancer Institute (NCI), to illustrate the construction of cellular and molecular three-dimensional atlases of human cancers as they evolve from precancerous lesions to advanced disease. We describe the collaborative nature of the network and the research to determine how and when premalignant lesions progress to invasive cancer, regress or obtain a state of equilibrium. We have attempted to highlight progress made by HTAN in building precancer atlases and discuss possible future directions. It is hoped that the lessons from our experience with HTAN will help other investigators engaged in the construction of precancer atlases to crystallize their thoughts on logistics, rationale, and implementation.

Integrated modeling of global change impacts on land and water resources.

There is a common scientific understanding that global change impact analysis, mitigation, and adaptation require interdisciplinary work. Integrated modeling could help to address the challenges associated with the impacts of global change. Particularly, integrated modeling that takes feedback effects into account will allow for the derivation of climate resilient land use and land management. Here, we call for more of such integrated modeling work focusing on the interdisciplinary subject of water resources and land management. As a proof-of-concept, we tightly couple a hydrologic (SWAT) and a land use model (CLUE-s) and illustrate the benefits of this coupled land and water modeling framework (LaWaCoMo) with a scenario on cropland abandonment induced by water stress. As compared to standalone model runs of SWAT and CLUE-s for the past, LaWaCoMo performs slightly better regarding measured river discharge (PBIAS: +0.8% and +1.5% compared at two gauges) and land use change (figure of merit: +6.4% and +2.3% compared to land use maps at two points in time). We show that LaWaCoMo is suitable for global change impact analysis as it is sensitive to climate and land use inputs as well as to management decisions. Our results shed light on the importance of feedback effects between land use and hydrology to assess impacts of global change on land and water resources accurately and consistently. To facilitate that the developed methodology can serve as a blueprint for integrated modeling of global change impacts, we used two freely available models that belong to the most widely used models in their respective disciplines.

Spatial and temporal assessment of human-water interactions at the Inle Lake, Myanmar: a socio-hydrological DPSIR analysis.

Freshwater resources as a key aspect of socio-economic development, provide a large number of services in human and environmental systems. Nevertheless, human appropriation of these water resources and the modification of landscapes lead to potential threats on water availability and quality from local to global scales. The Inle Lake in Myanmar is an economically, traditionally, and ecologically important freshwater ecosystem that faced severe degradation from the 2000s. In its catchment area, a Driver-Pressure-State-Impact-Response (DPSIR) framework is applied for an assessment period of 30 years from 1990 to 2020. The analysis results are complemented with a socio-hydrological survey, water quality assessment, a land use classification based on ground truth and satellite data, and hydrologic models. The resulting land use changes, - 13% forest, + 13% agriculture, and + 5% urban areas, lead to increased water yield, decreased evapotranspiration, and increased sediment yield. Together with other drivers and pressures such as climate change and anthropogenic pollution, these human activities are major threats for freshwater resources and the ecosystem. However, the existing awareness of the local population for the environmental degradation is obstructed by national and international crises and responses to negative developments can accelerate degradation if they are unplanned and short-term solutions. Our study shows that environmental degradation processes have a complex nature and can only be tackled in a coordinated way with a long-term perspective. DPSIR is a suitable approach to assess human-water dynamics and disentangle the complex interconnectedness of social and environmental systems in freshwater ecosystems, even in data-scarce regions.

Land use change and climate dynamics in the Rift Valley Lake Basin, Ethiopia.

Land use and climate dynamics have a pronounced impact on water resources, biodiversity, land degradation, and productivity at all scales. Thus, in this study, we present the spatio-temporal dynamics of land use change and climate aiming to provide a scientific evidence about gains and losses in major land use categories and associated drivers and significancy and homogeneity of climate change. To this end, Landsat images and historical climate data have been used to determine the dynamics. In addition, population census data and land use policy have been considered to assess the potential drivers of land use change. The spatio-temporal land use dynamics have been evaluated using transition matrix and dynamics index. Likewise, shifts in the climate data were analyzed using change point analysis and three homogenous climate zones have been identified using principal component analysis. The results show that, from 1989 to 2019, the areal percentage of agricultural land increased by 27.5%, settlement by 0.8%, and barren land 0.4% while the natural vegetation, wetland, water body, and grass land decreased by 24.5%, 1.6%, 0.5%, and 2.1%, respectively. The land use dynamics have been stronger in the first decade of the study period. An abrupt shift of climate has occurred in the 1980s. In the last four decades, rainfall shows a not significant decreasing trend. However, a significant increasing trend has been observed for temperature. Rapid population growth, agricultural expansion policy, and climate variability have been identified as the underlying drivers of land use dynamics.

Effects of Diets Enriched with Conventional or High-Oleic Canola Oils on Vascular Endothelial Function: A Sub-Study of the Canola Oil Multi-Centre Intervention Trial 2 (COMIT-2), a Randomized Crossover Controlled Feeding Study.

Partial replacement of saturated fatty acids (SFA) with unsaturated fatty acids is recommended to reduce cardiovascular disease (CVD) risk. Monounsaturated fatty acids (MUFA), including oleic acid, are associated with lower CVD risk. Measurement of flow-mediated dilation of the brachial artery (FMD) is the gold standard for measuring endothelial function and predicts CVD risk. This study examined the effect of partially replacing SFA with MUFA from conventional canola oil and high-oleic acid canola oil on FMD. Participants (n = 31) with an elevated waist circumference plus ≥1 additional metabolic syndrome criterion completed FMD measures as part of the Canola Oil Multi-Centre Intervention Trial 2 (COMIT-2), a multi-center, double-blind, three-period crossover, controlled feeding randomized trial. Diet periods were 6 weeks, separated by ≥4-week washouts. Experimental diets were provided during all feeding periods. Diets only differed by the fatty acid profile of the oils: canola oil (CO; 17.5% energy from MUFA, 9.2% polyunsaturated fatty acids (PUFA), 6.6% SFA), high-oleic acid canola oil (HOCO; 19.1% MUFA, 7.0% PUFA, 6.4% SFA), and a control oil blend (CON; 11% MUFA, 10% PUFA, 12% SFA). Multilevel models were used to examine the effect of the diets on FMD. No significant between-diet differences were observed for average brachial artery diameter (CO: 6.70 ± 0.15 mm, HOCO: 6.57 ± 0.15 mm, CON: 6.73 ± 0.14 mm; p = 0.72), peak brachial artery diameter (CO: 7.11 ± 0.15 mm, HOCO: 7.02 ± 0.15 mm, CON: 6.41 ± 0.48 mm; p = 0.80), or FMD (CO: 6.32 ± 0.51%, HOCO: 6.96 ± 0.49%, CON: 6.41 ± 0.48%; p = 0.81). Partial replacement of SFA with MUFA from CO and HOCO had no effect on FMD in participants with or at risk of metabolic syndrome.

A method for detecting the non-stationarity during high flows under global change.

The sustainability of existing water resources is influenced by extreme streamflow, and climate variability and human activities are generally the major factors controlling these dynamics. However, most of previously proposed methods to determine the effects of these factors have only been developed under the assumption of stationarity. Therefore, to overcome the existing research gap, an innovative method was proposed in this study to analyze and distinguish the effects of climate variability and human activities on extreme streamflow based on the non-stationarity theory. Accordingly, a rainfall-runoff model was developed using long-term hydrological data in the watersheds of Southeast China, which cover >75,000 km2. The model proposed in this study showed an acceptable performance, as indicated by the Nash-Sutcliffe efficiency coefficient (NSE), the Kling-Gupta efficiency (KGE), and percent bias (PBIAS). The NSE, KGE, and |PBIAS| were 0.67-0.75, 0.57-0.74, and 1.22-16.79 during the calibration periods, respectively. And the NSE, KGE, and |PBIAS| were 0.69-0.77, 0.65-0.76, and 0.98-17.51 during the calibration periods, respectively. The trends of the extreme streamflow were analyzed for these watersheds at different time scales. The streamflow extremes at short time scales were found to be more sensitive to changing environment than those at longer time scales. The major factor controlling streamflow extremes at short time scales was human activities and climate change may be the dominant factor influencing streamflow extremes at long time scales. The findings of this study could provide useful insights into water management under global change conditions.

Impacts of hydrological alteration on ecosystem services changes of a large river-connected lake (Poyang Lake), China.

Large lakes provide various types of ecosystem services (ESs), of which stocks and variations induced by hydrological alterations are largely unquantified. The present study investigates the long-term changes of five key ESs (i.e., flood regulation, water supply, fish production, nutrient retention and biodiversity conservation) in a large river connected lake (Poyang Lake), with special attention to impacts of hydrological alteration induced by the Three Gorges Dam (TGD). Hydrological data series, hydrodynamic model, the nutrient balance, fishery statistics, and wetland winter waterbird survey data from 1980 to 2016 were employed. Results showed that Poyang Lake provide significant ESs, with long-term average flood regulation, water supply and nutrient retention services of 167.7 × 108 m3, 31.53 × 108 m3, and 15.12% of total phosphorus load, respectively. The fish production service ranged from 1.74 × 104t to 7.19 × 104t, with an average value of 3.12 × 104t. All five key ESs exhibited a downward trend since the 2000s, especially for water supply, fish production and nutrient retention services (p < 0.05), which might be largely attributed to the hydrological condition changes induced by TGD operation. Nevertheless, more detailed monitoring data and biophysical models are required to further acknowledge the changes in biodiversity conservation and fish production services and their linkages with the TGD. The present study sheds light on long-term ES changes in large lakes and their possible linkages with human influences through hydropower projects.

Elucidating the combinatorial effect of substrate stiffness and surface viscoelasticity on cellular phenotype.

Cells maintain tensional homeostasis by monitoring the mechanics of their microenvironment. In order to understand this mechanotransduction phenomenon, hydrogel materials have been developed with either controllable linear elastic or viscoelastic properties. Native biological tissues, and biomaterials used for medical purposes, often have complex mechanical properties. However, due to the difficulty in completely decoupling the elastic and viscous components of hydrogel materials, the effect of complex composite materials on cellular responses has largely gone unreported. Here, we characterize a novel composite hydrogel system capable of decoupling and individually controlling both the bulk stiffness and surface viscoelasticity of the material by combining polyacrylamide (PA) gels with microgel thin films. By taking advantage of the high degree of control over stiffness offered by PA gels and viscoelasticity, in terms of surface loss tangent, of microgel thin films, it is possible to study the influence that bulk substrate stiffness and surface loss tangent have on complex fibroblast responses, including cellular and nuclear morphology and gene expression. This material system provides a facile method for investigating cellular responses to complex material mechanics with great precision and allows for a greater understanding of cellular mechanotransduction mechanisms than previously possible through current model material platforms.

APPARILLO: a fully operational and autonomous staring system for LEO debris detection.

For safe operation of active space crafts, the space debris population needs to be continuously scanned, to avoid collisions of active satellites with space debris. Especially the low Earth orbit (LEO) shows higher risks of collisions due to the highest density of orbital debris. Laser ranging stations can deliver highly accurate distance measurements of debris objects allowing precise orbit determination and more effective collision avoidance. However, a laser ranging station needs accurate a priori orbit information to track an orbital object. To detect and track unknown orbital objects in LEO, here, a passive optical staring system is developed for autonomous 24/7 operation. The system is weather-sealed and does not require any service to perform observations. To detect objects, a wide-angle imaging system with 10° field of view equipped with an astronomical CCD camera was designed and set up to continuously observe the sky for LEO objects. The system can monitor and process several passing objects simultaneously without limitations. It automatically starts an observation, processes the images and saves the 2D angular measurements of each object as equatorial coordinates in the TDM standard. This allows subsequent initial orbit determination and handover to a laser tracking system. During campaigns at twilight the system detected up to 36 objects per hour, with high detection efficiencies of LEO objects larger than 1 m3. It is shown that objects as small as 0.1 m3 can be detected and that the estimated precision of the measurements is about 0.05° or 7 × the pixel scale.

LARAMOTIONS: a conceptual study on laser networks for near-term collision avoidance for space debris in the low Earth orbit.

A conceptual study has been carried out on laser station networks to enhance Space Situational Awareness and contribute to collision avoidance in the low Earth orbit by high-precision laser tracking of debris objects and momentum transfer via photon pressure from ground-based high-power lasers. Depending on the network size, geographical distribution of stations, orbit parameters, and remaining time to conjunction, multipass irradiation enhances the efficiency of photon momentum coupling by 1-2 orders of magnitude and has the potential to eventually yield a promisingly significant reduction of the collision rate in low Earth orbit.

Twenty years of change: Land and water resources in the Chindwin catchment, Myanmar between 1999 and 2019.

Since 2011, Myanmar has undergone a more rapid socio-economic development, which may substantially have affected land use and land cover (LULC) and water resources. This study investigates the changes in land and water resources of the Chindwin River catchment (114,686.9 km2) in Myanmar over a twenty-year timespan from 1999 to 2019. The main aim of this study is to assess LULC change and evaluate its effects on the water balance and the people in the region. To this end, interviews were conducted, LULC classifications based on multi-temporal multi-spectral satellite data and in-situ ground truth data were created, and a hydrologic model was built. The hydrologic model shows a reasonable performance for daily discharge simulation at the catchment outlet (percent bias between -2 and 13.2, Kling-Gupta Efficiency between 0.75 and 0.76, Nash-Sutcliffe Efficiency between 0.57 and 0.61, RMSE-observations standard deviation between 0.63 and 0.66). The LULC changes detected include a decrease in forest area of about 2%, an increase in shrubland area indicating increased degradation of the forest, an increase in mining areas of 0.38%, an overall decrease in agricultural area (2.1%), but also the presence of new agricultural land pointing toward relocation of agricultural areas and an indication of an increase in settlement areas (1.5%). With the help of the hydrologic model, the most significant hydrologic impacts detected were a decrease in evapotranspiration and an increase in water yield which is correlated with the decrease of forest at the sub-catchment scale (R2 = 0.72 and 0.46, respectively). Moreover, an increase of mining areas contributed to the increase in water yield (R2 = 0.62). Interviews confirm that the identified LULC changes deforestation and increased mining activities contribute to major issues, e.g., water pollution, sedimentation, and changes in the river course.

Equity for and Inclusion of Non-Tenure-Track Pharmacy Faculty Within Academia.

Although there are at least twice as many non-tenure-track first-time pharmacy faculty as tenured and tenure-track first-time pharmacy faculty entering academia based on data collected from 2013 to 2019, there are ongoing equity, inclusion, and advancement issues between these categories of faculty that require consideration. Contracts with clear descriptions of responsibilities are needed along with regular evaluations and promotion opportunities based on the faculty member's performance of the assigned responsibilities, appropriate compensation including fringe benefits, inclusion in institutional voting and governance, and due process protections against abrupt termination. Further, universities and schools and colleges of pharmacy should foster a culture that values all faculty regardless of rank or position. The purpose of this commentary is to describe ongoing efforts and lessons learned by one public university with a college of pharmacy that has non-tenure-track and tenure-track faculty. Our hope is to provide insight into how these experiences could be used as a basis to inform changes in policy by other universities with a school or college of pharmacy, as well as to inform possible changes to the Academy's policies.

The Early Detection Research Network: A National Infrastructure to Support the Discovery, Development, and Validation of Cancer Biomarkers.

In 2000, the NCI (Rockville, MD) established the Early Detection Research Network (EDRN) to identify, develop, and validate biomarkers to improve the detection of early-stage cancers and risk assessment. This consortium of more than 300 investigators at academic institutions and in the private sector is working collaboratively to bring biomarkers and imaging methods to clinical fruition. Although significant roadblocks have hindered the field of biomarker discovery and validation, the EDRN has helped overcome many of them by setting well-defined strategies and milestones focused on solving defined unmet clinical needs. The EDRN has implemented measures to improve biomarker discovery and validation, such as data sharing, use of common data elements, generating multidisciplinary and multi-institutional collaborations within a cohesive and productive team environment, and putting emphasis on quality control and data replication for all candidate biomarkers for reaching a "go" or "no go" decision. A measure of the success of the EDRN is the number of biomarkers tests or devices approved by the FDA to which EDRN investigators have made significant contributions and the number of biomarkers tests developed by EDRN investigators that are available in Clinical Laboratory Improvement Amendments laboratories.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Effects of dynamic land use/land cover change on water resources and sediment yield in the Anzali wetland catchment, Gilan, Iran.

Land use/land cover (LULC) changes strongly affect catchment hydrology and sediment yields. The current study aims at analyzing the hydrological consequences of dynamic LULC changes in the Anzali wetland catchment, Iran. The Soil and Water Assessment Tool (SWAT 2012) model was used to assess impacts on evapotranspiration, water yield, and sediment yield. Two model runs were performed using static and dynamic LULC inputs to evaluate the effects of LULC change between 1990 and 2013. For the static model, the LULC map of 1990 was used, whereas for the dynamic model, a gradual change of the LULC distribution was interpolated from 1990, 2000, and 2013 LULC data. The major LULC changes were identified as an increase of agricultural area by 7% of the catchment area and a decrease of forest coverage by 6.8% between 1990 and 2013. At the catchment scale, the differences in the long-term mean annual values for the main water balance components and sediment yield were smaller than 10 mm (<2.8%) and 3 t/km2 (<2.6%), respectively. However, at the sub-basin scale the increase of agricultural land use resulted in an increase of evapotranspiration, water yield, and sediment yield by up to 8.3%, 7%, and 169%, respectively, whereas urban expansion led to a decrease of evapotranspiration, water yield, and sediment yield by up to -3.5%, -2.3%, and -9.4%. According to the results of the monthly time scale analysis, the most significant impact of LULC changes occurs during the dry season months, when the increase of irrigation agriculture results in an increase in water discharge and sediment loads to the Anzali wetland. Overall, the results showed that the implementation of dynamic LULC change into the SWAT model could be adopted as a planning tool to manage LULC change of the Anzali wetland catchment in the future.

Cancer overdiagnosis: a biological challenge and clinical dilemma.

For cancer screening to be successful, it should primarily detect cancers with lethal potential or their precursors early, leading to therapy that reduces mortality and morbidity. Screening programmes have been successful for colon and cervical cancers, where subsequent surgical removal of precursor lesions has resulted in a reduction in cancer incidence and mortality. However, many types of cancer exhibit a range of heterogeneous behaviours and variable likelihoods of progression and death. Consequently, screening for some cancers may have minimal impact on mortality and may do more harm than good. Since the implementation of screening tests for certain cancers (for example, breast and prostate cancers), a spike in incidence of in situ and early-stage cancers has been observed, but a link to reduction in cancer-specific mortality has not been as clear. It is difficult to determine how many of these mortality reductions are due to screening and how many are due to improved treatments of tumours. In cancers with lower incidence but high mortality (for example, pancreatic cancer), screening has focused on high-risk populations, but challenges similar to those for general population screening remain, particularly with regard to finding lesions with difficult-to-characterize malignant potential (for example, intraductal papillary mucinous neoplasms). More sensitive screening methods are detecting smaller and smaller lesions, but this has not been accompanied by a comparable reduction in the incidence of invasive cancers. In this Opinion article, we focus on the contribution of screening in general and high-risk populations to overdiagnosis, the effects of overdiagnosis on patients and emerging strategies to reduce overdiagnosis of indolent cancers through an understanding of tumour heterogeneity, the biology of how cancers evolve and progress, the molecular and cellular features of early neoplasia and the dynamics of the interactions of early lesions with their surrounding tissue microenvironment.