## Sources

1. [Optimizing KRAS Therapeutics for Non–Small Cell Lung Cancer](https://www.annualreviews.org/content/journals/10.1146/annurev-med-043024-115849?TRACK=RSS)
2. [Genomic Taxonomy of Aggressive B-Cell Lymphoid Neoplasms](https://www.annualreviews.org/content/journals/10.1146/annurev-pathmechdis-111523-023413?TRACK=RSS)
3. [Biased Signaling in Psychedelic Action](https://www.annualreviews.org/content/journals/10.1146/annurev-pharmtox-062124-012545?TRACK=RSS)
4. [Novel Advances in Our Understanding of Sex-Dependent Control of Blood Pressure](https://www.annualreviews.org/content/journals/10.1146/annurev-physiol-050724-022450?TRACK=RSS)

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### **Biased Signaling in Psychedelic Action**
**Authors:** Daniel Wacker and John D. McCorvy [1, 2]

*   **Main Arguments:**
    *   While it is established that the activation of the **serotonin 5-HT$_{2A}$ receptor** is essential for the psychopharmacological effects of psychedelics, the specific signaling pathways and receptor conformations that produce rapid and durable therapeutic effects versus adverse ones remain uncertain [2].
    *   The authors argue that **biased signaling**—the ability of a ligand to preferentially activate one signaling pathway over another (such as G protein vs. $\beta$-arrestin)—can be harnessed to develop "tailored" pharmacotherapies that separate therapeutic benefits from hallucinogenic or other side effects [2].
*   **Key Takeaways:**
    *   **Serotonin 5-HT$_{2A}$ receptors** are the primary target, but other 5-HT receptors may also play roles in shaping the overall therapeutic response [2].
    *   Advances in **structural biology** and the discovery of biased agonist tool compounds are providing a roadmap for designing psychedelic-derived drugs with improved safety profiles [2].
    *   There is a critical need for **rigor and reproducibility** in the field, drawing lessons from similar efforts in the opioid field (e.g., G protein-biased opioid agonists) to ensure successful clinical translation [2].
*   **Important Details:**
    *   Researchers are exploring **non-hallucinogenic analogs** (e.g., lisuride or specific LSD analogs) as tool compounds to investigate whether hallucinogenic effects are mandatory for antidepressant-like actions [3, 4].
    *   Specific pathways like the **$\beta$-arrestin 2/Src/Akt complex** or the **G$_{q}$ protein pathway** are under investigation for their respective roles in behavior and neural plasticity [3, 5].
    *   The review highlights **structural studies** of receptors bound to LSD and other ligands to understand the precise molecular triggers of biased signaling [6].

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### **Genomic Taxonomy of Aggressive B-Cell Lymphoid Neoplasms**
**Authors:** Laura K. Hilton, Brett Collinge, and David W. Scott [7, 8]

*   **Main Arguments:**
    *   Current classification systems for aggressive B-cell lymphomas, which utilize over 20 categories based on morphology and immunophenotype, do not fully capture the biological reality of the disease [9].
    *   The authors propose a shift toward a **genomics-informed taxonomy** centered on the stages of **normal B-cell development** (particularly the germinal center) and the specific genomic hallmarks that drive malignancy [9].
*   **Key Takeaways:**
    *   The largest clinical category, **diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)**, is remarkably heterogeneous at the genomic level, which explains varying treatment responses [9].
    *   Genomic profiling can identify **core biological hallmarks**—such as specific gene expression signatures (e.g., GCB vs. ABC subtypes)—that are more reliable for informing patient management and prognosis than traditional morphology [9, 10].
    *   Identifying **founder mutations** and structural variants (like *MYC* and *BCL2* rearrangements) is essential for refining these diagnostic categories [11, 12].
*   **Important Details:**
    *   **Germinal center (GC) dynamics** are central to understanding lymphomagenesis; most aggressive B-cell lymphomas originate from B cells during different phases of the GC reaction [11, 13].
    *   The **"double-hit" signature** (rearrangements of *MYC* and *BCL2*) defines a particularly high-risk subgroup of patients that requires distinct therapeutic approaches [12].
    *   Novel classifications are increasingly incorporating **probabilistic molecular classifiers** (e.g., DLBclass) to guide clinical investigation [14].

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### **Novel Advances in Our Understanding of Sex-Dependent Control of Blood Pressure**
**Authors:** Rachel Q. Muir, Jiaojiao Xu, Alexandra D. Medcalf, and Jennifer L. Pluznick [15, 16]

*   **Main Arguments:**
    *   Significant **sex differences in blood pressure (BP)** regulation exist, with premenopausal females typically exhibiting lower BP than males; however, these differences shift after menopause [17].
    *   BP regulation is a highly integrated process, and sex differences arise from complex interactions between the nervous system, kidneys, immune cells, the microbiome, and the **renin-angiotensin-aldosterone system (RAAS)** [17].
*   **Key Takeaways:**
    *   Hormonal factors are primary drivers: **estrogen** generally exerts protective, BP-lowering effects, while **androgens** like testosterone can contribute to arterial stiffening and higher BP [18, 19].
    *   Beyond hormones, the **sex chromosome complement** (XX vs. XY) independently influences BP, as shown in models like the four-core genotype (FCG) [17, 18].
    *   Novel regulators such as the **G protein-coupled estrogen receptor (GPER)**, the anti-aging protein **Klotho**, and **olfactory receptor 558 (OLFR558)** have emerged as critical, sex-specific mediators of BP [17, 20-22].
*   **Important Details:**
    *   The **gut microbiome** shows sex-specific resistome profiles and contributes to BP regulation through the production of metabolites like short-chain fatty acids [20, 23].
    *   **T-lymphocytes** play a sex-specific role in hypertension; for example, regulatory T-cells (Tregs) provide a protective effect in females that is lost after menopause [23, 24].
    *   **Arterial stiffness** accelerates more rapidly in women within one year of their final menstrual period, highlighting the impact of the menopausal transition on vascular health [19].

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### **Optimizing KRAS Therapeutics for Non–Small Cell Lung Cancer**
**Authors:** Jeong Uk Lim, Marcelo V. Negrao, and David S. Hong [25, 26]

*   **Main Arguments:**
    *   The treatment of **KRAS-mutant non–small cell lung cancer (NSCLC)** has undergone a paradigm shift with the successful development of inhibitors targeting the once "undruggable" KRAS protein [26].
    *   While first-generation **G12C inhibitors** (sotorasib and adagrasib) have improved clinical outcomes, their long-term efficacy is severely limited by the emergence of **acquired resistance** [26].
*   **Key Takeaways:**
    *   Acquired resistance often occurs through secondary *KRAS* mutations or the reactivation of bypass signaling pathways, such as the **RAS-MAPK or PI3K/AKT pathways** [26, 27].
    *   Future progress depends on **combination strategies**—pairing KRAS inhibitors with immunotherapy, SHP2 inhibitors, or other targeted agents—to overcome feedback loops and suppress resistance [26, 27].
    *   There is an urgent need to expand therapeutic options to include **non-G12C mutations** (e.g., G12D, G12V), which represent a large portion of KRAS-mutant NSCLC cases [26, 28].
*   **Important Details:**
    *   **Sotorasib** was the first G12C inhibitor to receive approval, followed by **adagrasib**, which has shown notable efficacy in patients with central nervous system (CNS) metastases [29].
    *   Next-generation inhibitors, such as **divarasib** and **olomorasib**, are being evaluated for potentially higher potency and improved safety profiles [28].
    *   Research is also moving toward **pan-KRAS inhibitors** and "multi-RAS" inhibitors that target the active (ON) state of the protein rather than just the inactive (OFF) state [27, 28].