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]


Background {#Sec1}
==========

Sex cord-stromal tumors represent approximately 8% of all ovarian tumors \[[@CR1]\]. The incidence is about 0.2 per 100000 women. The most frequently diagnosed tumor type within sex cord-stromal category is the granulosa cell tumor \[[@CR1]\]. Granulosa cell tumors may be composed almost exclusively of granulosa cells, but more commonly also contain theca cells, lutein cells, and/or fibroblasts \[[@CR2]\]. The granulosa cells in tumor may be arranged in trabecular, insular, grand like, microfollicular, macrofollicular or diffuse cellular patterns \[[@CR3]\]. Granulosa cell tumors can be further categorized into two distinct subtypes, juvenile and adult forms \[[@CR1]\]. Juvenile granulosa cell tumor is characterized by a modular or diffuse pattern, with follicle-like spaces of variable size and shape and striking cytologic atypia \[[@CR3]\]. In some cases, these tumors cannot be distinguished from each other or from other malignant tumors. Recent studies of *FOXL2* (forkhead box L2) gene 402C \> G (C134W) mutation may resolve the problems of adult-type granulosa cell tumor diagnosis \[[@CR4]\]. Adult-type granulosa cell tumors are much more common and mostly occur in perimenopausal or early postmenopausal females \[[@CR5]\].

Granulosa cell tumors are generally considered to have a better prognosis than epithelial ovarian tumors \[[@CR1]\]. However, there is high rate of tumor recurrence late in life and approximately 80% of patients with advanced stage or recurrent tumors succumb to their disease \[[@CR6]\]. Granulosa cell tumors with malignant potential comprise 1.0 percent of all ovarian cancers \[[@CR1]\]. The characteristics associated with granulosa cell tumors cannot be explained by ploidy or p53 overexpression \[[@CR7],[@CR8]\].

Case report {#Sec2}
===========

An 80-year-old woman presented with a clinically detectable pelvic mass. She subsequently underwent laparotomy for total hysterectomy and bilateral salpingo-oophorectomy. Gross examination demonstrated an ovarian mass with attached fallopian tube, measuring 11.0 × 8.0 × 7.0 cm, which was brownish in color and elastic. On cut, the ovary was yellowish in color and soft. Microscopically, the ovary revealed a granulosa-theca cell tumor characterized by granulosa cells in trabecular or cylindrical pattern and theca cells in spindle pattern (Figure [1](#Fig1){ref-type="fig"}). FIGO stage IA was supported by pathological report. Her blood inhibin A and B levels were 47.208 pg/ml and 92.473 pg/ml, respectively, immediately after operation and 15.533 pg/ml and 22.331 pg/ml, respectively, one month post-operation. No recurrent disease was noted during 3-year post-operation follow-up period. The Institutional Review Board of Chung Shan Medical University Hospital approved all procedures and informed consent was obtained prior to collecting her genetic material for the study.Figure 1**Granulosa cell tumor: Histological cross-section after hematoxylin and eosin staining shows the adult granulosa cell tumor component.**

We tested for the presence of *FOXL2* 402C \> G mutation using PCR and direct sequencing according to the methods described by Schrader et al \[[@CR9]\]. The nucleotide sequence analysis of *FOXL2* from the granulosa cell tumor section revealed heterozygous 402C \> G mutation. In contrast, *FOXL2* sequences of genomic DNA isolated from the blood and normal tissue of this patient did not demonstrate this mutation. When compared with DNA from normal cells (Figure [2](#Fig2){ref-type="fig"}A), DNA replication error caused by slippage between the replication apparatus and the DNA template was detected in the granulosa cell tumor (Figure [2](#Fig2){ref-type="fig"}B), on analysis of the lengths of CAG repeats in androgen receptor gene, using published primers and experimental conditions \[[@CR10]\]. In addition, we compared the DNA profiles of normal tissue and tumor tissue using short tandem repeats (STR) analysis according to the methods described by Wang et al \[[@CR11]\]. The tumor showed loss of heterozygosity (LOH) for a number of markers (Figure [3](#Fig3){ref-type="fig"} and Table [1](#Tab1){ref-type="table"}). Moreover, based on array comparative genomic hybridization (CGH), pathological genetic imbalances were detected in the tumor on CytoChip Oligo Array (BlueGenome): monosomy 4 and 10; partial monosomy 14 with segmental deletions; and mosaic trisomy 6, 11, 12, 13, 15, and 18 with segmental duplications (Figure [4](#Fig4){ref-type="fig"} and Table [2](#Tab2){ref-type="table"}).Figure 2**Replication error was detected on analysis of the CAG repeats in androgen receptor gene by capillary gel electrophoresis.** DNA from tumor **(B)** is compared with DNA from normal cells **(A)** from the same patient.Figure 3**LOH for a number of markers: Selective electrophoregram of the DNA profiles of blood and tumor tissue using short tandem repeats (STR) analysis with AmpFlSTR SGM Plus PCR amplification kit.** Colored panels are representative of the following: **(A)** STR loci of D8S1179, D21S11, D7S820, and CSF1PO; **(B)** STR loci of D19S433 and vWA; **(C)** STR loci of D3S1358 and D2S1338.Table 1**Loss of heterozygosity in 15 STR loci of the granulosa cell tumorSTR LociLocationAllelesR** ^**a**^TPOX2p23-2per8, 8NDD2S13382q35-37.122, 231.63^b^D3S13583p21.3115, 161.84^b^FGA4q2822, 231.01D5S8185q21-3111, 11NDCSF1PO5q33.3-3410, 111.86^b^D7S8207q11.21-2210, 120.56^b^D8S11798q24.1-24.211, 11NDTH0111p15.59, 9NDvWA12p12-pter14, 181.14D13S31713q22-3110, 130.94D16S53916q24-qter9, 111.11D18S5118q21.314, 181.06D19S43319q12-13.113, 141.81^b^D21S1121q11.2-q2130, 31.22.12^ba^R = (area T1/area T2)/(area N1/area N2); ^b^Loss of heterozygosity (LOH) is positive when R ≥ 1.25 or ≤ 0.8 (ie., 20% change).Figure 4**Array comparative genomic hybridization (aCGH) analysis: Whole genome view on comparative genomic hybridization array (CytoChip Oligo Array) shows pathological genetic imbalances in many chromosomes in the tumor.**Table 2**The deleted or duplicated clones and their physical location in the granulosa cell tumorISCN nomenclatureTypeSize (bp)**1arr 4p16.3q35.2(37,152-190,896,645)×1LOSS190,859,4932arr 6p25.3q27(163,113-170,921,060)×2 \~ 3GAIN170,757,9473arr 10p15.3q26.3(136,391-135,434,149)×1LOSS135,297,7584arr 11p15.5q25(196,990-134,868,378)×2 \~ 3GAIN134,671,3885arr 12p13.33q24.33(230,451-133,773,499)×2 \~ 3GAIN133,543,0486arr 13q12.11q34(20,407,324-115,092,619)×2 \~ 3GAIN94,685,2957arr 14q11.2q32.33(20,608,246-107,287,476)×1LOSS86,679,2308arr 15q11.1q26.3(20,686,219-102,383,444)×2 \~ 3GAIN81,697,2259arr 16q11.2q24.3(46,500,771-90,148,364)×1 \~ 2LOSS43,647,59310arr 18p11.32q23(148,993-78,012,800)×2 \~ 3GAIN77,863,807

Discussion {#Sec3}
==========

Recent studies have shown that *FOXL2* 402C \> G is a diagnostic characteristic of adult-type granulosa cell tumor \[[@CR4]\]. However, little is known about how a granulosa cell tumor undergoes indolent course with late recurrent behavior \[[@CR12]\]. We report a case of adult-type granulosa cell tumor with *FOXL2* 402C \> G mutation in an 80-year-old woman, in which one allele was normal and one was mutant. This mutation was not observed in the blood and normal tissue samples of this patient. Histological diagnosis is compatible with adult-type granulosa cell tumor in this case. RNA transcription arrays from granulosa cell tumor cell line have indicated that alteration involves cell death, proliferation and tumorigenesis \[[@CR13]\]. However, the mechanism is not clear.

DNA replication error on analysis of the lengths of CAG repeats in androgen receptor gene (Figure [2](#Fig2){ref-type="fig"}B) is consistent with a previous study suggesting that a DNA mismatch repair deficiency contributes to the pathogenesis of granulosa cell tumors, and that this deficiency is an early event in their development and/or progression \[[@CR14]\]. LOH for a number of markers (Table [1](#Tab1){ref-type="table"} and Figure [3](#Fig3){ref-type="fig"}) and pathological genetic imbalances throughout the genome (Table [2](#Tab2){ref-type="table"} and Figure [4](#Fig4){ref-type="fig"}) imply that a defective upstream regulatory gene is involved in this condition. The *MLH1* gene that encodes a component of the mismatch repair system located near the D3S1358 locus showed LOH (Table [1](#Tab1){ref-type="table"}). This implies that the upstream regulatory mechanisms leading to increased DNA replication errors, LOH, and genetic imbalances are associated with defect(s) in global gene regulation.

Our assumption is that a genetic alteration in mismatch repair system occurs before *FOXL2* 402C \> G mutation. After this mutation is initiated, granulosa cell tumor develops in early tumorigenesis. The genomic imbalances on array CGH in this study were inconsistent with the results of other array and CGH studies \[[@CR15]\]. However, there was a similar trend of genetic imbalances with a loss of 16q. These genetic imbalances may contribute to late tumorigenesis. Our hypothesis is that a DNA repair system failure induces *FOXL2* 402C \> G mutation, followed by granulosa cell tumor development. The same mechanism randomly causes further mutations of tumor suppressor genes or oncogenes, resulting in late recurrence and unpredictable malignant behavior of granulosa cell tumor. However, we cannot dismiss the possibility that the amino acid changing mutation in *FOXL2* 402C \> G is the driver mutation that leads to subsequent genomic alterations in granulosa cell tumor pathogenesis.

Conclusions {#Sec4}
===========

Adult-type granulosa cell tumors are associated with *FOXL2* 402C \> G mutation. In addition to this unique *FOXL2* mutation, we found DNA replication error and loss of heterozygosity in this case. DNA mismatch repair system failure appears likely in this patient. In such a case, early detection allows for treatment of benign tumor. Although this study could not elucidate the exact mechanism for the development of granulosa cell tumor, it does suggest the need to incorporate DNA mismatch repair system examination into the clinical management of patients with granulosa cell tumor.

Consent {#Sec5}
=======

Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

**Competing interests**

The authors declare that they have no competing interests.

**Authors' contributions**

YCL designed the experiments, performed the experiments, interpreted the results, and drafted the manuscript. WWC designed the experiments, provided samples and clinical data, interpreted the results and made critical revisions to the manuscript. Both authors have read and approved the final manuscript.