You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Targeted signaling inhibitors have improved treatment options for many cancers, but resistance mediated by redundancies in pathways limits clinical efficacy \[[@R1]\]. Activation of eIF4F, the complex that carries out cap-dependent translation initiation, is a convergence of multiple upstream oncogenic signals and drives resistance to targeted inhibitors (Figure [1](#F1){ref-type="fig"}) \[[@R2]\]. The complex comprises the cap-binding protein eIF4E, the scaffold protein eIF4G, and eIF4A, a DEAD-box RNA helicase responsible for unwinding secondary structures in mRNA transcripts. In 2004, the Pelletier group employed a bicistronic mRNA reporter to screen for eukaryotic protein translation inhibitors \[[@R3]\]. The reporter permitted multiplexed screening that distinguished between activity against cap-dependent initiation, IRES-mediated initiation, and elongation/termination. A series of compounds with specific activities against cap-dependent initiation emerged and were characterized in detail in the decade that followed. These include most notably the natural compounds hippuristanol, pateamine A, and the rocaglate silvestrol \[[@R4], [@R5]\]. All these compounds have the same molecular target, eIF4A, the ATP-dependent enzymatic core of the eIF4F complex. This activity is associated with potent anti-tumor activity, best characterized for silvestrol. Silvestrol binds to free (non-complexed) eIF4A and increases its affinity for mRNA in a sequence-specific manner, leading to a stable ternary complex, and preventing enzymatic unwinding of the secondary structure. G-quadruplexes and polypurine stretches of RNA in the 5'UTR exhibit greater binding by eIF4A-silvestrol and other rocaglates, and there is decreased translation of mRNAs harboring these characteristics \[[@R6], [@R7]\]. *In vivo* studies, including our group's recent work (detailed below), have established a therapeutic window for targeting the eIF4F complex \[[@R8], [@R9]\]. Overall, this body of work has clearly established eIF4A as a "privileged" target in cancer therapeutics preclinically, but to date no compound with this activity has made it to clinical evaluation. That may at last be about to change.

![Many pro-oncogenic signaling pathways converge on cap-dependent translation and can be inhibited by targeting eIF4A](oncotarget-09-35515-g001){#F1}

Biopharmaceutical company eFFECTOR Therapeutics is at the frontier of drug development for targeting translation with plans to begin phase I clinical trials (early 2019) using compound eFT226, a selective translation regulator. Meeting abstracts indicate that *in silico* models including ab initio ligand-based methods and analysis of crystal structures were used in the compound design. Preclinical data on eFT226 is not yet published, but a poster presented at the American Society of Hematology meeting in 2017 suggests a mechanism of action similar to the rocaglates, in which the compound increases the affinity of eIF4A for the mRNA in a sequence specific manner. While these results suggest a promising candidate, we must await peer-reviewed published data for thorough evaluation of the compound's mode-of-action. If able to successfully enter phase 1, however, eFT226 could be the first selective regulator of translation initiation to begin human trials and could set the stage clinically for a new class of anticancer therapeutics \[[@R10]\].

We took a different approach to eIF4A, exploiting its established status as a privileged target and carried out pilot target-based screening. Our recently published identification and characterization of the marine-derived natural compound elatol as a potent inhibitor of eIF4A with *in vivo* antitumor activity establishes proof-of-principle of our target-based approach \[[@R9]\]. We used an initial cell-free screen to identify inhibitors of eIF4A ATPase activity. Based on its relatively potent antitumor activities, elatol was further characterized and found to inhibit eIF4A helicase activity, and showed no activity against other tested ATP-hydrolyzing enzymes, including other DEAD box helicases, or kinases. Although less potent than silvestrol, elatol exhibited antitumor activity across a panel of cancer cell lines, with leukemias and lymphomas most sensitive overall. Assessment of effect on translation inhibition revealed that elatol preferentially inhibits cap-dependent translation compared to IRES-mediated translation, and experiments using elatol to treat tumor-bearing mouse xenografts established a therapeutic window *in vivo*. Off-target effects, including induction of an integrated stress response for unclear reasons, and limited opportunities for optimization through medicinal chemistry have halted further work on elatol specifically. However, this work provides proof of principle for a pipeline to identify eIF4A inhibitors starting with a cell-free target-based approach that measures inhibition of ATPase activity and to further characterize these hits *in vitro* and *in vivo*.

Moving forward, we are carrying out high-throughput screening employing an optimized platform that simultaneously assesses all three paralogs of eIF4A (eIF4A1-3). eIF4A1 is the key player in cap-dependent initiation, and our work to date suggests identifying off-target activity against the closely homologous but biologically distinct paralogs eIF4A2 and eIF4A3 will be important in optimizing drug candidates. Compounds considered hits in our cell-free ATPase inhibition assay are taken through a series of biochemical, cell-based, and when appropriate *in vivo* verification steps. These include eIF4A1 helicase inhibition, binding analyses with mutagenesis confirmation, assessment of preference for inhibition of cap-dependent vs. IRES-mediated translation, and of course assessments of anti-tumor potency. *In vivo* experiments are used to determine maximum tolerated dose of compounds and their effect on tumor growth in xenograft and immunocompetent tumor models. Our high throughput, target-based screen and downstream confirmatory drug pipeline with mechanistic studies will enable us to screen thousands of compounds and to identify eIF4A1-specific protein translation inhibitors. With cancer resistance and relapse to targeted signaling inhibitors still major clinical issues, the emergence of an eIF4A1-targeted clinical candidate in our opinion reveals a substantial new opportunity for cancer drug development. We and others are committed to seeing this treatment approach finally achieve testing in cancer patients. Our focus is on establishment and ongoing refinements of a pipeline able to narrow in on the most promising novel inhibitors of eIF4A-mediated protein translation. Targeting regulatory mechanisms of protein translation, the convergence point of many oncogenic signaling pathways, is a rational approach to killing cancer cells with functionality of many oncoproteins and pro-survival factors being lost or diminished.