Alina didn’t stay in the ward like other patients; she stayed at the Sanbo Hotel.
Every morning at 7:30, she would appear punctually at the Institute building, first drawing blood, then going to the imaging departnt for the day’s scheduled examinations. In the afternoon, she would circulate between various platforms, collecting single-cell sequencing samples, conducting tabolomics analyses, and even participating in several brain functional MRI scans to assess the effects of regulatory treatnt on the central nervous system’s stress response.
Before the second infusion, the results of the colonoscopy follow-up ca out.
"Thirty-seven adenomas, the number hasn’t decreased, but the morphology has changed." Director Xiao from the endoscopy center at Sanbo Hospital personally reported to Yang Ping.
The images of the adenomas before and after treatnt were displayed side by side on the screen, "Before treatnt, the vascular textures on the surface of these adenomas were disordered, with unclear boundaries, showing the typical sawtooth appearance. And now, the vascular textures of twenty-three of the adenomas have beco orderly, with clear boundaries, more akin to benign tubular adenomas. Pathological biopsy also confird this: cellular atypia was reduced, and nuclear mitotic figures decreased."
"From high-grade intraepithelial neoplasia to low-grade?"
"You could understand it that way." Director Xiao’s tone was incredulous, "Just with a single low-dose K therapy, there is already a trend of pathologic reversal. Although the adenomas are still there, they seem to be reversing towards healthy cells."
The most crucial data ca from single-cell sequencing. Tang Shun’s team analyzed eight thousand cells from the colonic mucosa before and after treatnt and discovered a subtle but consistent pattern change:
Before treatnt, cell populations were scattered in the "identity state space," the TIM expression profile exhibited high entropy features, like a noisy hall where everyone spoke loudly yet could not hear the content.
After treatnt, a "clustering" trend appeared in the distribution of cell populations, with a 15% decrease in the entropy of the TIM expression profile. More importantly, there was a weak negative correlation between the expression levels of the previously disordered "pre-apoptotic components" genes and the TIM expression level, which is exactly the logical relationship in normal tissues: cells with stable identity don’t need to be constantly ready for self-removal.
"The system is re-establishing order." Tang Shun showed a heat map at the discussion eting, "Though still very preliminary, the direction is clear."
Yang Ping stared at the gradually changing blocks of color, thinking of Alina’s analogy of "tuning." A disordered instrunt with chaotic vibration frequencies of its strings produces harsh noise; after tuning, harmonious relationships between frequencies allow the instrunt to produce pleasing sounds. Now Alina’s colonic mucosal cells seem to be transitioning from noise to harmony.
But just before the start of the second infusion, Alina had an unexpected reaction.
Diarrhea, five to six tis a day, watery stools, but without abdominal pain or fever, and slight instability in the control of the little finger on her right hand.
Examinations showed her serum potassium level at the lower limit of normal, intestinal inflammation indicators slightly elevated, but infection markers negative.
"Is this a treatnt-related response?" Song Zimo worriedly asked.
Yang Ping reviewed all the data, repeatedly comparing before proposing his judgnt: "It’s not a side effect, but part of the regulatory process."
He had the team focus on analyzing the single-cell data from Alina’s colon biopsy during the period of diarrhea. The results revealed a dramatic change: just 48 hours before the symptoms appeared, a specific subgroup of cells in the colon epithelium, about 3% of the total, suddenly overexpressed various ion channel proteins and water transport proteins, accompanied by a brief downregulation of tight junction proteins.
"These cells...are actively increasing intestinal secretion, reducing...barrier function?" Xu Zhiliang was puzzled, "Why?"
"Clearance!" Yang Ping pointed to another finding, "In this group of cells, TIM expression levels dropped sharply, while autophagy-related genes were significantly upregulated. Look here, LC3 fluorescence labeling shows a massive autophagy occurring inside these cells."
He integrated all the clues, depicting a possible scene: Unlike dealing with late-stage tumors, after the body’s system restores recognition of these cells’ identity, it finds that so cells have slight variations, prompting a kind of reversal regulation that makes these cells reverse towards healthy cells; while another part of the cells may have already crossed the reversal threshold, initiating a "clearance" program. The clearance thod is by altering their own functions, promoting the expulsion of intestinal contents to flush themselves out.
The human body is truly marvelous; its thods surpass the current dical techniques significantly. The future of dicine should make good use of the body’s self-correction capabilities.
To verify this hypothesis, the team designed an experint: in an organoid model, treating Alina’s colonic organoids with different doses of regulatory agents. At low doses, the overall structure of the organoids is more orderly, and the expression of cell identity genes is more consistent; but when the dose exceeds a certain threshold, it indeed induces so cells to undergo similar functional changes and autophagy.
"There is a threshold," Tang Shun summarized, "Beyond this threshold, reversal is impossible, only clearance, while within the threshold, try to reverse as much as possible. Also, for this precancerous lesion, if the dose is too large, the system’s bias towards clearance might increase, while the attempt to reverse might decrease."
Based on this, Yang Ping’s team adjusted Alina’s second infusion dose down by 20%.
After the adjustnt, the diarrhea symptoms disappeared within two days, and the subsequent colonoscopy showed further "benignization" of adenomas. More importantly, the TIM expression profile’s entropy further decreased by 10%, and the indicators of system stability continued to improve.
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