Distribution shift detection for the postmarket surveillance of medical AI algorithms: a retrospective simulation study.

Distribution shifts remain a problem for the safe application of regulated medical AI systems, and may impact their real-world performance if undetected. Postmarket shifts can occur for example if algorithms developed on data from various acquisition settings and a heterogeneous population are predominantly applied in hospitals with lower quality data acquisition or other centre-specific acquisition factors, or where some ethnicities are over-represented. Therefore, distribution shift detection could be important for monitoring AI-based medical products during postmarket surveillance. We implemented and evaluated three deep-learning based shift detection techniques (classifier-based, deep kernel, and multiple univariate kolmogorov-smirnov tests) on simulated shifts in a dataset of 130'486 retinal images. We trained a deep learning classifier for diabetic retinopathy grading. We then simulated population shifts by changing the prevalence of patients' sex, ethnicity, and co-morbidities, and example acquisition shifts by changes in image quality. We observed classification subgroup performance disparities w.r.t. image quality, patient sex, ethnicity and co-morbidity presence. The sensitivity at detecting referable diabetic retinopathy ranged from 0.50 to 0.79 for different ethnicities. This motivates the need for detecting shifts after deployment. Classifier-based tests performed best overall, with perfect detection rates for quality and co-morbidity subgroup shifts at a sample size of 1000. It was the only method to detect shifts in patient sex, but required large sample sizes ( > 3 0 ' 000 ). All methods identified easier-to-detect out-of-distribution shifts with small (≤300) sample sizes. We conclude that effective tools exist for detecting clinically relevant distribution shifts. In particular classifier-based tests can be easily implemented components in the post-market surveillance strategy of medical device manufacturers.

An evolutionarily conserved mechanism controls reversible amyloids of pyruvate kinase via pH-sensing regions.

Amyloids are known as irreversible aggregates associated with neurodegenerative diseases. However, recent evidence shows that a subset of amyloids can form reversibly and fulfill essential cellular functions. Yet, the molecular mechanisms regulating functional amyloids and distinguishing them from pathological aggregates remain unclear. Here, we investigate the conserved principles of amyloid reversibility by studying the essential metabolic enzyme pyruvate kinase (PK) in yeast and human cells. We demonstrate that yeast PK (Cdc19) and human PK (PKM2) form reversible amyloids through a pH-sensitive amyloid core. Stress-induced cytosolic acidification promotes aggregation via protonation of specific glutamate (yeast) or histidine (human) residues within the amyloid core. Mutations mimicking protonation cause constitutive PK aggregation, while non-protonatable PK mutants remain soluble even upon stress. Physiological PK aggregation is coupled to metabolic rewiring and glycolysis arrest, causing severe growth defects when misregulated. Our work thus identifies an evolutionarily conserved, potentially widespread mechanism regulating functional amyloids during stress.

Yield reduction caused by elevated temperatures and high nitrogen fertilization is mitigated by SP6A overexpression in potato (Solanum tuberosum L.).

Potatoes (Solanum tuberosum L.) are a fundamental staple for millions of people worldwide. They provide essential amino acids, vitamins, and starch - a vital component of the human diet, providing energy and serving as a source of fiber. Unfortunately, global warming is posing a severe threat to this crop, leading to significant yield losses, and thereby endangering global food security. Industrial agriculture traditionally relies on excessive nitrogen (N) fertilization to boost yields. However, it remains uncertain whether this is effective in combating heat-related yield losses of potato. Therefore, our study aimed to investigate the combinatory effects of heat stress and N fertilization on potato tuber formation. We demonstrate that N levels and heat significantly impact tuber development. The combination of high N and heat delays tuberization, while N deficiency initiates early tuberization, likely through starvation-induced signals, independent of SELF-PRUNING 6A (SP6A), a critical regulator of tuberization. We also found that high N levels in combination with heat reduce tuber yield rather than improve it. However, our study revealed that SP6A overexpression can promote tuberization under these inhibiting conditions. By utilizing the excess of N for accumulating tuber biomass, SP6A overexpressing plants exhibit a shift in biomass distribution towards the tubers. This results in an increased yield compared to wild-type plants. Our results highlight the role of SP6A overexpression as a viable strategy for ensuring stable potato yields in the face of global warming. As such, our findings provide insights into the complex factors impacting potato crop productivity.

INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas.

Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis. Finally, we show that GNAQ/11-mutant UM cells and patients' tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.

Prospective randomized pilot study of a novel patient-centered pathology report for colorectal polyps.

Objective: US patients have increased access to their medical records, yet the information is not always understandable. To improve patient understanding, we tested a patient-centered pathology report (PCPR) containing results for recent colon cancer screening or surveillance colonoscopy. Methods: A pilot randomized trial assessed the impact of addition of the PCPR to a standard pathology report on knowledge accuracy, decisional self-efficacy and control, and therapeutic alliance. Results: 55 participants were enrolled; 20 participants in the intervention group and 24 controls completed follow-up. There was no significant difference in polyp knowledge between groups at baseline or 30-days, with similar confidence in understanding their diagnoses, decisional self-efficacy, and therapeutic alliance. Most participants receiving a PCPR felt that it helped them understand their diagnosis better and should always be provided with the standard pathology report. Conclusion: Although patient attitudes toward the PCPR were positive, receiving it did not significantly improve knowledge accuracy or measures of self-efficacy. Further iterations should be explored to communicate key knowledge about colorectal polyp results. Innovation: A stakeholder-driven approach to PCPR development facilitated construction of a personalized document that has potential to increase patient's understanding for their results and needed follow-up.

A reference assembly for the legume cover crop hairy vetch (Vicia villosa).

Vicia villosa is an incompletely domesticated annual legume of the Fabaceae family native to Europe and Western Asia. V. villosa is widely used as a cover crop and forage due to its ability to withstand harsh winters. Here, we generated a reference-quality genome assembly (Vvill1.0) from low error-rate long-sequence reads to improve the genetic-based trait selection of this species. Our Vvill1.0 assembly includes seven scaffolds corresponding to the seven estimated linkage groups and comprising approximately 68% of the total genome size of 2.03 Gbp. This assembly is expected to be a useful resource for genetically improving this emerging cover crop species and provide useful insights into legume genomics and plant genome evolution.

Single-cell Profiling Uncovers a Muc4-Expressing Metaplastic Gastric Cell Type Sustained by Helicobacter pylori-driven Inflammation.

Mechanisms for Helicobacter pylori (Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant Hp infection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA sequencing showed that Hp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin Muc4 and the growth factor amphiregulin. Flow cytometry and IHC-based immune profiling revealed that metaplastic pit cells were associated with macrophage and T-cell inflammation. Accordingly, expansion of metaplastic pit cells was prevented by gastric immunosuppression and reversed by antibiotic eradication of Hp. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an Hp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by Hp-dependent inflammation. Significance: Using a mouse model, we have delineated metaplastic pit cells as a precancerous cell type whose expansion requires Hp-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.

Multi-pilot implementation experiences of patient-centered pathology reports: lessons learned for the advancement of patient-centered tools for cancer decision-making.

PURPOSE: New federal legislation in the United States grants patients expanded access to their medical records, making it critical that medical records information is understandable to patients. Provision of informational summaries significantly increase patient perceptions of patient-centered care and reduce feelings of uncertainty, yet their use for cancer pathology is limited. METHODS: Our team developed and piloted patient-centered versions of pathology reports (PCPRs) for four cancer organ sites: prostate, bladder, breast, and colorectal polyp. The objective of this analysis was to identify common barriers and facilitators to support dissemination of PCPRs in care delivery settings. We analyzed quantitative and qualitative data from pilot PCPR implementations, guided by the RE-AIM framework to explore constructs of reach, effectiveness, adoption, implementation, and maintenance. RESULTS: We present two case studies of PCPR implementation - breast cancer and colorectal polyps-that showcase diverse workflows for pathology reporting. Cross-pilot learnings emphasize the potential for PCPRs to improve patient satisfaction, knowledge, quality of shared decision-making activities, yet several barriers to dissemination exist. CONCLUSION: While there is promise in expanding patient-centered cancer communication tools, more work is needed to expand the technological capacity for PCPRs and connect PCPRs to opportunities to reduce costs, improve quality, and reduce waste in care delivery systems.

Pathology Education Powered by Virtual and Digital Transformation: Now and the Future.

CONTEXT.­: Myriad forces are changing teaching and learning strategies throughout all stages and types of pathology education. Pathology educators and learners face the challenge of adapting to and adopting new methods and tools. The digital pathology transformation and the associated educational ecosystem are major factors in this setting of change. OBJECTIVE.­: To identify and collect resources, tools, and examples of educational innovations involving digital pathology that are valuable to pathology learners and teachers at each phase of professional development. DATA SOURCES.­: Sources were a literature review and the personal experience of authors and educators. CONCLUSIONS.­: High-quality digital pathology tools and resources have permeated all the major niches within anatomic pathology and are increasingly well applied to clinical pathology for learners at all levels. Coupled with other virtual tools, the training landscape in pathology is highly enriched and much more accessible than in the past. Digital pathology is well suited to the demands of peer-to-peer education, such as in the introduction of new testing, grading, or other standardized practices. We found that digital pathology was well adapted to apply our current understanding of optimal teaching strategies and was effective at the undergraduate, graduate, postgraduate, and peer-to-peer levels. We curated and tabulated many existing resources within some segments of pathology. We identified several best practices for each training or educational stage based on current materials and proposed high-priority areas for potential future development.

SF3B1 facilitates HIF1-signaling and promotes malignancy in pancreatic cancer.

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between the expression levels of wild-type SF3B1 and tumor malignancy. Here, we demonstrate that SF3B1 is a hypoxia-inducible factor (HIF)-1 target gene that positively regulates HIF1 pathway activity. By physically interacting with HIF1α, SF3B1 facilitates binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. To further validate the relevance of this mechanism for tumor progression, we show that a reduction in SF3B1 levels via monoallelic deletion of Sf3b1 impedes tumor formation and progression via impaired HIF signaling in a mouse model for pancreatic cancer. Our work uncovers an essential role of SF3B1 in HIF1 signaling, thereby providing a potential explanation for the link between high SF3B1 expression and aggressiveness of solid tumors.

Preclinical Testing of Boron-Doped Diamond Electrodes for Root Canal Disinfection-A Series of Preliminary Studies.

While numerous approaches have meanwhile been described, sufficient disinfection of root canals is still challenging, mostly due to limited access and the porous structure of dentin. Instead of using different rinsing solutions and activated irrigation, the electrolysis of saline using boron-doped diamond (BDD) electrodes thereby producing reactive oxygen species may be an alternative approach. In a first step, experiments using extracted human teeth incubated with multispecies bacterial biofilm were conducted. The charge quantities required for electrochemical disinfection of root canals were determined, which were subsequently applied in an animal trial using an intraoral canine model. It could be shown that also under realistic clinical conditions, predictable disinfection of root canals could be achieved using BDD electrodes. The parameters required are in the range of 5.5 to 7.0 V and 9 to 38 mA, applied for 2.5 to 6.0 min with approximately 5 to 8 mL of saline. The direct generation of disinfective agents inside the root canal seems to be advantageous especially in situations with compromised access and limited canal sizes. The biologic effect with respect to the host reaction on BDD-mediated disinfection is yet to be examined.

Comparing the electrophysiological effects of traumatic noise exposure between rodents.

Noise-induced hearing deficits are important health problems in the industrialized world. As the underlying physiological dysfunctions are not well understood, research in suitable animal models is urgently needed. Three rodent species (Mongolian gerbil, rat, and mouse) were studied to compare the temporal dynamics of noise-induced hearing loss after identical procedures of noise exposure. Auditory brainstem responses (ABRs) were measured before, during, and up to 8 wk after noise exposure for threshold determination and ABR waveform analysis. Trauma induction with stepwise increasing sound pressure level was interrupted by five interspersed ABR measurements. Comparing short- and long-term dynamics underlying the following noise-induced hearing loss revealed diverging time courses between the three species. Hearing loss occurred early on during noise exposure in all three rodent species at or above trauma frequency. Initial noise level (105 dB SPL) was most effective in rats whereas the delayed level increase to 115 dB SPL affected mice much stronger. Induced temporary threshold shifts in rats and mice were larger in animals with lower pretrauma ABR thresholds. The increase in activity (gain) along the auditory pathway was derived by comparing the amplitudes of short- and long-latency ABR waveform components. Directly after trauma, significant effects were found for rats (decreasing gain) and mice (increasing gain) whereas gerbils revealed high individual variability in gain changes. Taken together, our comparative study revealed pronounced species-specific differences in the development of noise-induced hearing loss and the related processing along the auditory pathway.NEW & NOTEWORTHY We compared deficits after noise trauma in different rodents that are typically used in hearing research (Mongolian gerbil, rat, and mouse). We observed noise-induced threshold changes and alterations in the activity of processing auditory information along the ascending auditory pathway. Our results reveal pronounced differences in the characteristics of trauma-induced damage in these different rodent groups.

Chromosome-scale assembly of the highly heterozygous genome of red clover (Trifolium pratense L.), an allogamous forage crop species.

Relative to other crops, red clover (Trifolium pratense L.) has various favorable traits making it an ideal forage crop. Conventional breeding has improved varieties, but modern genomic methods could accelerate progress and facilitate gene discovery. Existing short-read-based genome assemblies of the ∼420 megabase pair (Mbp) genome are fragmented into >135,000 contigs, with numerous order and orientation errors within scaffolds, probably associated with the plant's biology, which displays gametophytic self-incompatibility resulting in inherent high heterozygosity. Here, we present a high-quality long-read-based assembly of red clover with a more than 500-fold reduction in contigs, improved per-base quality, and increased contig N50 by three orders of magnitude. The 413.5 Mbp assembly is nearly 20% longer than the 350 Mbp short-read assembly, closer to the predicted genome size. We also present quality measures and full-length isoform RNA transcript sequences for assessing accuracy and future genome annotation. The assembly accurately represents the seven main linkage groups in an allogamous (outcrossing), highly heterozygous plant genome.

Implementation and Effectiveness of a Completely Virtual Pathology Rotation for Visiting Medical Students.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) upended in-person medical education, relocating many activities online. We designed a completely virtual pathology rotation to replace our traditional visiting rotation. METHODS: The virtual away rotation was listed in the Visiting Student Application Service (VSAS) and advertised on social media as well as various medical student mailing lists. Nine students were selected to participate in three month-long rotations. The virtual curriculum mirrored our typical in-person clerkship with didactic lectures and daily signout but also included activities exclusive to the virtual rotation such as digitally scanned slide trays and small-group problem-based learning. Anonymous surveys were conducted in which both participants and instructors rated their experiences. RESULTS: Postrotation feedback was overwhelmingly positive from both participants and instructors. Students considered virtual slide sessions as the most effective teaching tool and did not feel hindered overall by lack of in-person experiences. Volunteer trainee instructors indicated the experience improved their teaching and diagnostic skills and expressed interest in teaching future virtual courses. CONCLUSIONS: The success of the virtual away rotation raises consideration for applications beyond the pandemic era and may provide a more level playing field for medical students from underrepresented groups.

Measuring Gait Stability in People with Multiple Sclerosis Using Different Sensor Locations and Time Scales.

The evaluation of local divergence exponent (LDE) has been proposed as a common gait stability measure in people with multiple sclerosis (PwMS). However, differences in methods of determining LDE may lead to different results. Therefore, the purpose of the current study was to determine the effect of different sensor locations and LDE measures on the sensitivity to discriminate PwMS. To accomplish this, 86 PwMS and 30 healthy participants were instructed to complete a six-minute walk wearing inertial sensors attached to the foot, trunk and lumbar spine. Due to possible fatigue effects, the LDE short (~50% of stride) and very short (~5% of stride) were calculated for the remaining first, middle and last 30 strides. The effect of group (PwMS vs. healthy participants) and time (begin, mid, end) and the effect of Expanded Disability Status Scale (EDSS) and time were assessed with linear random intercepts models. We found that perturbations seem to be better compensated in healthy participants on a longer time scale based on trunk movements and on a shorter time scale (almost instantaneously) according to the foot kinematics. Therefore, we suggest to consider both sensor location and time scale of LDE when calculating local gait stability in PwMS.

Medical Education in Pathology: General Concepts and Strategies for Implementation.

CONTEXT.­: Pathology education must evolve as medical knowledge expands and disruptive technologies emerge. The evolution in pathology teaching practices accelerated as traditional teaching modalities were suspended in March 2020 during the coronavirus disease 2019 (COVID-19) pandemic. OBJECTIVES.­: To provide pathologists an overview of established teaching paradigms and practical examples of how these paradigms may be applied to pathology education, emphasizing differences in graduate and undergraduate medical education as well as the challenges and promises of remote learning, as revealed by the COVID-19 pandemic. DATA SOURCES.­: Selected peer-reviewed publications representing the field of educational social science. CONCLUSIONS.­: Evidence-based methods described in education and social sciences can be effectively deployed in pathology education and especially remote learning, as necessitated by the current COVID-19 pandemic. Understanding established principles, such as cognitive load, competency-based learning, peer-assisted learning, and flipped classrooms may prove useful in developing effective, learner-centric content for pathology education.

Interobserver agreement in pathologic evaluation of bile duct biopsies.

Intraductal biopsy is commonly used for preoperative evaluation of the etiology of biliary strictures. Interpretation of intraductal biopsies is frequently challenging. The diagnosis often suffers from interobserver disagreement, which has not been studied in the literature. We sought to assess interobserver concordance in the interpretation of intraductal biopsies. Eighty-five biopsies were retrieved, falling into five diagnostic categories: negative for dysplasia (NED), indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and carcinoma (CA). Eight gastrointestinal pathologists blindly reviewed all the slides. Agreement among pathologists was analyzed using Fleiss κ and weighted concordance coefficient S∗. A face-to-face consensus/training session was held to discuss the classification criteria, followed by a second round review. The overall interobserver agreement was fair in the first round review (κ = 0.39; S∗ = 0.56) and improved to moderate in the second round review (κ = 0.48; S∗ = 0.69). The agreement before and after consensus meeting was substantial to nearly perfect for CA (κ = 0.65, S∗ = 0.83; and κ = 0.80, S∗ = 0.91), fair for HGD (κ = 0.28, S∗ = 0.69; and κ = 0.40, S∗ = 0.63), and moderate for NED (κ = 0.47, S∗ = 0.50; and κ = 0.47, S∗ = 0.53). Agreement improved from fair to moderate for LGD (κ = 0.36, S∗ = 0.61; and κ = 0.49, S∗ = 0.71) and slight to fair for IND (κ = 0.16, S∗ = 0.51; and κ = 0.33, S∗ = 0.50). Compared with Hollande's fixed specimens, the agreement was higher in almost all diagnostic categories in formalin-fixed biopsies. Overall, interobserver concordance was improved after a consensus/training session. Interobserver reproducibility was high at the end of the diagnostic spectrum (CA) but fair to moderate for other diagnostic categories.

Cytosolic pH regulates proliferation and tumour growth by promoting expression of cyclin D1.

Enhanced growth and proliferation of cancer cells are accompanied by profound changes in cellular metabolism. These metabolic changes are also common under physiological conditions, and include increased glucose fermentation accompanied by elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we show that elevated pHc specifically orchestrates an E2F-dependent transcriptional programme to drive cell proliferation by promoting cyclin D1 expression. pHc-dependent transcription of cyclin D1 requires the transcription factors CREB1, ATF1 and ETS1, and the histone acetyltransferases p300 and CBP. Biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH sensor and coincidence detector, integrating different mitotic signals to regulate cyclin D1 transcription. We also show that elevated pHc contributes to increased cyclin D1 expression in malignant pleural mesotheliomas (MPMs), and renders these cells hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression, and provide a mechanism linking elevated pHc to oncogenic activation of cyclin D1 in MPMs, and possibly other cyclin D1~dependent tumours. Thus, an increase of pHc may represent a functionally important, early event in the aetiology of cancer that is amenable to therapeutic intervention.

Bats as putative Zaire ebolavirus reservoir hosts and their habitat suitability in Africa.

The genus Ebolavirus comprises some of the deadliest viruses for primates and humans and associated disease outbreaks are increasing in Africa. Different evidence suggests that bats are putative reservoir hosts and play a major role in the transmission cycle of these filoviruses. Thus, detailed knowledge about their distribution might improve risk estimations of where future disease outbreaks might occur. A MaxEnt niche modelling approach based on climatic variables and land cover was used to investigate the potential distribution of 9 bat species associated to the Zaire ebolavirus. This viral species has led to major Ebola outbreaks in Africa and is known for causing high mortalities. Modelling results suggest suitable areas mainly in the areas near the coasts of West Africa with extensions into Central Africa, where almost all of the 9 species studied find suitable habitat conditions. Previous spillover events and outbreak sites of the virus are covered by the modelled distribution of 3 bat species that have been tested positive for the virus not only using serology tests but also PCR methods. Modelling the habitat suitability of the bats is an important step that can benefit public information campaigns and may ultimately help control future outbreaks of the disease.

Another Consequence of the Warburg Effect? Metabolic Regulation of Na+/H+ Exchangers May Link Aerobic Glycolysis to Cell Growth.

To adjust cell growth and proliferation to changing environmental conditions or developmental requirements, cells have evolved a remarkable network of signaling cascades that integrates cues from cellular metabolism, growth factor availability and a large variety of stresses. In these networks, cellular information flow is mostly mediated by posttranslational modifications, most notably phosphorylation, or signaling molecules such as GTPases. Yet, a large body of evidence also implicates cytosolic pH (pHc) as a highly conserved cellular signal driving cell growth and proliferation, suggesting that pH-dependent protonation of specific proteins also regulates cellular signaling. In mammalian cells, pHc is regulated by growth factor derived signals and responds to metabolic cues in response to glucose stimulation. Importantly, high pHc has also been identified as a hall mark of cancer, but mechanisms of pH regulation in cancer are only poorly understood. Here, we discuss potential mechanisms of pH regulation with emphasis on metabolic signals regulating pHc by Na+/H+-exchangers. We hypothesize that elevated NHE activity and pHc in cancer are a direct consequence of the metabolic adaptations in tumor cells including enhanced aerobic glycolysis, generally referred to as the Warburg effect. This hypothesis not only provides an explanation for the growth advantage conferred by a switch to aerobic glycolysis beyond providing precursors for accumulation of biomass, but also suggests that treatments targeting pH regulation as a potential anti-cancer therapy may effectively target the result of altered tumor cell metabolism.