Jigish

Family man with passion to learn more about this amazing human body and investing in BIOTECHS

[Jigish @jigpika]

@AjTrader7 AJ, you did again!! TSLA SHORT from 323 to 321. Done for the week. Join the ACT room if you are serious about day trading

[Jigish @jigpika]

@endless_frank Valuation matters, why are you so worried if you have 10
year horizon?

[Jigish @jigpika]

@davey_juice What do you think now? I guess you timed the top nicely :) That is why you follow the charts and not business is telling you as it is lagging indicator, by then the market has already priced the future

[Jigish @jigpika]

@davey_juice What do you think the business will tell you otherwise :) Remember they need to create the hype or their stock craters. That why semiconductor companies are notorious cyclical :)

[Jigish @jigpika]

@AjTrader7 AJ, you are the best mentor & trader I have come in my last 10 years of trading. Look at the TSLA notes from today: You said, if it snaps 320, look for nice 5-8pt sell off. It gave more than 10 points. I met my weekly goal of 5k. For serious day traders, Join ACT room

[Rose Celine Investments 🌹 @realroseceline]

The Invisible Transfer

One of the biggest investing mistakes sounds completely logical. Find an extraordinary business, hold it for a long time, and exceptional returns will naturally follow. It feels almost impossible to lose, yet this simple assumption has probably cost investors more money than almost any other mistake.

Imagine a business is intrinsically worth $100 per share today. Over the next 10 years, it compounds its intrinsic value at an incredible 20% annually. By the end of the decade, that same business is now worth $620 per share.

Now imagine 3 investors all buy that business and hold it for the next 10 years, and they all watch the same management team make the same decisions. The only difference is the price each investor was willing to pay.

The first investor pays $100 because that’s what the business is worth. The second investor becomes excited and pays $200 because he’s convinced it’s a once in a generation company. The third investor becomes even more optimistic and pays $300 because he simply “has to own it”.

Now assume that after 10 years, the market recognizes the company’s intrinsic value and the stock trades at $620 per share. Nothing about the business disappointed. It compounded at 20% annually, strengthened its competitive advantage, generated mountains of cash, and became one of the greatest businesses in the world.

Yet their investment results couldn’t be more different. The investor who paid $100 earned 20% annually because he captured nearly all of the company’s compounding. The investor who paid $200 earned only 12% per year, while the investor who paid $300 earned 7.5% annually, despite owning the exact same business for 10 years. — Here’s the math: Annual return = (Ending value ÷ Starting value)^(1 ÷ Years) − 1

Think about how remarkable that is. Three investors owned the exact same company, for the exact same length of time, while management made the exact same decisions. One earned nearly three times the annual return of another because of a decision made on the very first day.

The business didn’t create different returns. The purchase price did. Most investors spend their time asking one question. How big can this company become? That’s certainly important, but it isn’t the most important question. A much better question is this: How big must this company become just to justify today’s stock price?

Those two questions sound almost identical, yet they produce completely different investment decisions. One focuses on the business, the other focuses on the investment. Great investors understand that those are not the same thing.

Now let’s make the example even more interesting. Imagine investors believed this business would compound at 35% annually for the next decade. Instead, it “only” compounded at 20% per year. Who was wrong?

Certainly not the business. A company that compounds its intrinsic value at 20% for 10 consecutive years is top tier and extraordinarily rare. Management executed brilliantly, customers remained loyal, margins expanded, and free cash flow continued growing year after year.

The problem wasn’t the company. The problem was that investors had already paid for something even better. They weren’t buying a business capable of compounding at 20%. They were paying as though they were buying one that would compound at 35%.

That’s one of the strangest truths in investing. A business can produce extraordinary results and still become a disappointing investment. Not because the company failed, but because the expectations embedded in the stock price were even more extraordinary.

This is why I believe expectations behave like a hidden form of debt. It never appears on the balance sheet, yet it can become one of the largest liabilities a company carries. The higher the valuation climbs, the more future perfection the business owes investors simply to justify where the stock already trades.

1/2

[Jigish @jigpika]

@AjTrader7 AJ, .. I love to trade with you every day in the ACT chatroom, every week. I have been in your room for last 3 years. Your daily commentary and notes are a BEAST every day. My goal is 5k for the week. Love you BOSS!!! You are the best mentor and trader!!!

[Jigish @jigpika]

@linasbeliunas @kingofhuntleyvj

[Jigish @jigpika]

@linasbeliunas @VijayPa83647397 check this link

[Jigish @jigpika]

@DavidLinthicum @VijayPa83647397

[Jigish @jigpika]

@ShamikaRavi @VijayPa83647397

[Jigish @jigpika]

@AjTrader7 It has been a blessing trading with you every day in https://t.co/puGASOxeLc. Your knowledge and expertise help so many traders like me. Follow the NOTES and make money day after day. Thanks Boss!

[Guardian Research @thegresearch]

Read this one if you read nothing else from me. You're on one of three paths right now. You cannot afford to be on the wrong one.

[In Honour Of Thomas W Phelps @HOThomasWPhelps]

$CRVS Explanation I have been working on to explain #soquelitinib durability in atopic dermatitis w/ 90% of patients showing AD remission still 90 days post-treatment due to novel short-term Signal 1 interference v other Signal 3 blocking approaches = leading to "immune reset" and long-lived iTregs for durable disease control.

My hypothesis below fits w/ comments from Corvus they are seeing changes in JAK/STAT pathway and Tregs that they will disclose at SID in May.

My thoughts:
"A mechanistic hypothesis that selective ITK inhibition stabilizes induced FOXP3+ Tregs through suppression of the IL-4/STAT6 epigenetic destabilization axis"

Background:
Induced regulatory T cells, or iTregs, are an attractive therapeutic concept in autoimmune and inflammatory disease because they offer the possibility of restoring immune balance rather than merely suppressing downstream inflammation. In principle, a durable increase in stable FOXP3+ suppressive T cells could reset the relationship between effector and regulatory immunity and produce benefits that persist after treatment ends. In practice, however, iTregs are often unstable. Inflammatory cytokine environments can weaken FOXP3 expression, reduce suppressive function, and permit reversion toward effector phenotypes. This fragility is a central limitation of many immune-rebalancing strategies.

A particularly important destabilizing pathway is the IL-4/STAT6 axis. IL-4 promotes #Th2 polarization, but it also acts as an antagonist of iTreg differentiation and maintenance. Through IL-4Rα and downstream #JAK/#STAT6 signaling, inflammatory Th2 conditions can oppose the establishment of a stable FOXP3 program. This is relevant because durable Treg biology depends not only on transient induction of FOXP3, but on maintenance of an epigenetic state at the FOXP3 locus that supports continued transcription and resists inflammatory reprogramming.

Selective ITK inhibition raises a potentially important question in this context. ITK sits upstream in T-cell receptor signaling (Signal 1) and is especially important for programs that support inflammatory helper T-cell differentiation, including Th2 and Th17 responses. If selective ITK inhibition reduces Th2-driving circuitry and IL-4 production while also favoring Treg-skewed differentiation, it may influence both the generation and the long-term stability of induced FOXP3+ Tregs. That possibility leads to my central hypothesis: selective ITK inhibition may stabilize induced FOXP3+ Tregs through suppression of the IL-4/STAT6 epigenetic destabilization axis.

Mechanistic Model - The proposed model has two linked stages:
The first stage is differentiation bias. Selective ITK inhibition weakens proximal TCR signaling (i.e., CD28) and thereby reduces support for inflammatory effector programs, especially Th2 and Th17 differentiation. In parallel, this signaling shift may favor the emergence of FOXP3+ induced Tregs. In this sense, ITK inhibition may function as a lineage-biasing intervention, moving the immune system away from inflammatory helper states and toward a more regulatory balance.

The second stage is stability. This stage may be the more important or most important for explaining durable benefit. The model proposes that selective ITK inhibition reduces GATA-3 (strongly shown by Corvus) and IL-4 output from effector T cells, which in turn lowers activation of the IL-4Rα-JAK-STAT6 pathway. Reduced STAT6 signaling then relieves a major source of iTreg destabilization. Under these conditions, induced FOXP3+ Tregs may be more likely to preserve an epigenetic state compatible with durable lineage identity.

Next, three candidate regulatory nodes I have identified seem especially relevant in this framework. First, reduced STAT6 signaling may lower #DNMT1 activity or expression, helping preserve demethylation of the FOXP3 Treg-specific demethylated region and supporting continued FOXP3 transcription. Second, reduced IL-4/STAT6 signaling may decrease #HDAC9 activity or expression, favoring retention of histone acetylation across key FOXP3 regulatory elements such as CNS1 and CNS2. Third, histone acetyltransferase (#HAT1) activity may become relatively favored, potentially increasing chromatin accessibility at the FOXP3 locus. The combined effect would be a more transcriptionally open FOXP3 region, more persistent FOXP3 expression, and a more stable suppressive iTreg phenotype.

This model does not require ITK inhibition to bind directly to chromatin regulators. Instead selective ITK inhibition may act upstream of the epigenetic program by changing the cytokine and transcription-factor environment that determines whether induced Tregs remain stable or become plastic.

Supporting Evidence in Literature:
Several lines of evidence support this framework, although they do not yet establish the full mechanism.

1. ITK biology supports the differentiation component of the model. ITK is a key signaling node downstream of the TCR and has a recognized role in inflammatory helper T-cell differentiation. Studies of ITK-deficient or ITK-inhibited systems support the idea that dampening ITK can shift the balance away from inflammatory effector programs and toward regulatory phenotypes. Avery August paper even showed that CPI-818 (soquelitinib) inhibition of ITK act like a switch diverting Th17 destined effector T-cells to the regulatory iTreg phenotype. This provides a plausible basis for the idea that selective ITK inhibition may increase formation of induced FOXP3+ Tregs in vivo.

2. The IL-4/STAT6 pathway is a credible destabilization axis for iTregs. IL-4 is not merely a Th2 cytokine; it also interferes with Treg differentiation and stability. Work on IL-4/STAT6 signaling has shown that this pathway can reduce Foxp3-associated chromatin accessibility and promote epigenetic conditions unfavorable for stable Treg identity. This makes STAT6 an especially meaningful intermediate between altered cytokine signaling and altered FOXP3 stability.

3. Epigenetic control of the FOXP3 locus is known to be central to Treg persistence. Stable Treg identity is associated with an accessible and appropriately demethylated FOXP3 locus, including key regulatory regions such as CNS1, CNS2, and the Treg-specific demethylated region (#TSDR). By contrast, transient or unstable FOXP3 induction is more vulnerable to loss under inflammatory conditions. This literature strongly supports the general principle that durable Treg function requires more than temporary transcriptional activation.

4. Prior work suggests that STAT6-deficient settings favor more suppressive Treg biology. Even Ibrutinib has shown to do this. Studies in STAT6-deficient systems have shown increased Treg abundance and the ability of relatively modest Treg increases to reduce allergic inflammation and impair recruitment of inflammatory effector T cells into tissues. Additional work has linked reduced STAT6 signaling to more favorable FOXP3-associated epigenetic states, including reduced DNMT1-related pressure. These findings do not prove the soquelitinib mechanism, but they strengthen the plausibility of the pathway being proposed.

5. Transcriptomic work in ITK-deficient T cells has identified changes in genes related to chromatin regulation, including HDAC9 and HAT1-associated signals. These findings are hypothesis-generating rather than definitive, but they support the idea that ITK biology may intersect with epigenetic regulators relevant to FOXP3 stability. In particular, the directionality of reduced HDAC9 and increased acetyltransferase-related signaling is consistent with a more open FOXP3 chromatin state.

Taken together, these strands support a coherent upstream-to-downstream logic: ITK inhibition may reduce inflammatory T-cell programming and IL-4 production; reduced IL-4 may dampen STAT6 activation; reduced STAT6 activity may lessen epigenetic pressure against stable FOXP3 expression; and the resulting iTregs may be more durable and suppressive than iTregs generated under inflammatory conditions.

What I am watching for that we may hear about at SID:
1. Whether selective ITK inhibition with soquelitinib reduces IL-4/STAT6 signaling in relevant immune compartments and pSTAT6 in the relevant human T-cell and Treg compartments to a biologically meaningful degree. This is central to the hypothesis.

2. Whether DNMT1, HDAC9, and HAT2 acetyltransferase-related pathways actually change in the predicted direction within induced Tregs generated under soquelitinib exposure.

3. Related to FOXP3 locus specificity including FOXP3 TSDR methylation analysis, chromatin accessibility testing such as ATAC-seq, and chromatin immunoprecipitation or related assays for histone acetylation across the FOXP3 promoter, CNS1, and CNS2, TSDR regions. This would establish whether the proposed upstream signaling changes actually produce the predicted local epigenetic consequences.

4. Whether any induced Tregs formed under ITK inhibition remain stable after drug withdrawal and inflammatory rechallenge. This is arguably the most important question of all. The hypothesis is ultimately about durability. It is not enough to show more FOXP3+ cells on drug. It must be shown that these cells retain FOXP3 expression and suppressive function after washout, particularly when exposed again to destabilizing cytokines such as IL-4.

5. If data supports formation of stable iTreg lineage conversion, not merely transient FOXP3 induction. Many systems can increase FOXP3 expression temporarily without generating truly stable suppressive cells. A durable clinical effect would require stable iTregs, but Corvus already seeing a durable effect in atopic dermatitis which is highly suggestive they are.

The current framework is best presented as a mechanistic hypothesis with strong biologic coherence and literature support and high potential significance/benefit, but not yet as an established mechanism. Together, such data would convert the current model from a plausible hypothesis into a mechanistically supported explanation for post-treatment durability.

Conclusion:
Selective ITK inhibition may have effects that extend beyond transient anti-inflammatory suppression. A coherent mechanistic model is that it first biases T-cell differentiation toward induced FOXP3+ regulatory states and away from inflammatory helper programs, then stabilizes those induced Tregs indirectly by suppressing the IL-4/STAT6 axis that normally drives epigenetic destabilization. In that setting, reduced DNMT1 and HDAC9 pressure, along with a more accessible FOXP3 locus, could help maintain persistent FOXP3 expression and durable suppressive function.

The significance of this hypothesis is HIGH because, if validated, it would offer a biologically plausible explanation for benefit that persists beyond active dosing. It would also position selective ITK inhibition as a true "immune-rebalancing strategy" rather than simply another anti-cytokine or downstream suppressive approach that reverses as soon as treatment is stopped.

If my hypothesis is validated, it is potentially game-changing not just for atopic dermatitis but for a broad range of I&I indications because it would move soquelitinib out of the standard “anti-inflammatory suppressor” bucket and into an “immune reset/stability-restoration” bucket. That is a much bigger claim. Scientifically, it would suggest that ITK inhibition is upstream enough (Signal 1) to alter not just cytokine output but the long-term lineage stability of suppressive T cells. Therapeutically, that would support intermittent dosing and off-drug durability rather than simple chronic suppression. This would be a revolutionary approach and paradigm shift in treatment of auto-immune diseases.

[Pharmdca @Pharmdca]

$CRVS May 14th- Data and Investor call. ⬇️⬇️

[Jigish @jigpika]

@HOThomasWPhelps Hello, Big fan of your research on Crvs. Sorry to hear about your mother. Hope god bless your family and she has a speedy recovery.

[Jigish @jigpika]

@HOThomasWPhelps Thank you!!! Had the same thoughts but wanted to confirm as no one has done better research on this drug than YOU! Thank you!!!

[Jigish @jigpika]

@HOThomasWPhelps Hello, Big fan of your research and big holder of CRVS. Do you see any safety concerns after looking at GR3 events, especially liver and congestive failure including others in the PTCL presentation?

[In Honour Of Thomas W Phelps @HOThomasWPhelps]

$CRVS $KYMR Maybe, but STAT6 knockout mice showed metabolic problems under high-fat diet conditions leading to liver steatosis as STAT6 is pleiotropic and in so many cells and tissues. Further STAT6 KO also resulted in exacerbation of some Th17 diseases like EAE, think MS. In fact, if you compared ITK knockout mice as a model for $CRVS ITK inhibitor soquelitinib and STAT6 KO mice as model for $KYMR KT-621 STAT6 degrader ITK KO mice has less health problems.

Overall Prediction: For human autoimmune therapy, single ITK inhibitor > STAT6 degrader in safety/AE profile. STAT6's broader disruptions and presence in more cells may make it riskier for chronic use.
Clinical monitoring (e.g., liver function, infection surveillance) would mitigate, but mouse data favors ITK kinase targeting for fewer off-target events for autoimmune diseases.

[Ted Zhang @TedHZhang]

Quote of the Day:

"Always focus on defense to stay in the game. They key to making money is keeping money. Making money is easy. Keeping and protecting capital is the hardest aspect of trading."

~ @Qullamaggie