Signal Transduction and Targeted Therapy最新文献

In a recent study, published in Nature, Nordmann et al. identified Janus kinase inhibitors (JAKi) as a new treatment option for life-threatening toxic epidermal necrolysis (TEN). They showed this through spatial proteomics on human skin samples combined with in vivo administration of JAKi in individuals with TEN, demonstrating rapid reepithelization and recovery of patients.¹ As TEN has a high mortality rate (30–50%),² this study offers a new avenue for targeted treatment.

The ongoing COVID-19 pandemic has underscored the importance of strong immune defenses against emerging SARS-CoV-2 variants. While COVID-19 vaccines containing XBB subvariants have proven effective in neutralizing new SARS-CoV-2 variants, a gap remains in knowledge regarding neutralizing antibody responses in older adults aged >65 years against these newly emerged variants. This study was therefore undertaken to investigate and compare neutralizing antibody responses to three XBB-containing protein-based vaccines (trivalent XBB.1.5 vaccine, bivalent Omicron XBB vaccine, and tetravalent XBB.1 vaccine) head-to-head in 90 individuals aged >65 years. The results showed that all three XBB-containing vaccines substantially enhanced the neutralizing antibody response, with 100% of vaccinees having detectable antibody titers against ancestral D614G and variants BA.5, XBB.1.5, JN.1, KP.2, and KP.3 after booster immunization. Subsequent analysis indicated that the trivalent XBB.1.5 and tetravalent XBB.1 vaccines elicited higher levels of neutralizing antibodies compared to the bivalent Omicron XBB vaccine. The KP.2 and KP.3 variants displayed antibody resistance comparable to the JN.1 variant. Older adults produce similar neutralizing antibody responses to the vaccines regardless of their underlying medical conditions. These findings indicate that booster vaccination with XBB-containing vaccines can effectively elicit strong neutralizing responses against a number of SARS-CoV-2 variants in older adults over 65 years, which will help guide vaccine strategies in this elderly population.

As essential micronutrients, metal ions such as iron, manganese, copper, and zinc, are required for a wide range of physiological processes in the brain. However, an imbalance in metal ions, whether excessive or insufficient, is detrimental and can contribute to neuronal death through oxidative stress, ferroptosis, cuproptosis, cell senescence, or neuroinflammation. These processes have been found to be involved in the pathological mechanisms of neurodegenerative diseases. In this review, the research history and milestone events of studying metal ions, including iron, manganese, copper, and zinc in neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), will be introduced. Then, the upstream regulators, downstream effector, and crosstalk of mental ions under both physiologic and pathologic conditions will be summarized. Finally, the therapeutic effects of metal ion chelators, such as clioquinol, quercetin, curcumin, coumarin, and their derivatives for the treatment of neurodegenerative diseases will be discussed. Additionally, the promising results and limitations observed in clinical trials of these metal ion chelators will also be addressed. This review will not only provide a comprehensive understanding of the role of metal ions in disease development but also offer perspectives on their modulation for the prevention or treatment of neurodegenerative diseases.

The potential benefits of pyrotinib for patients with trastuzumab-insensitive, HER2-positive early-stage breast cancer remain unclear. This prospective, multicentre, response-adapted study evaluated the efficacy and safety of adding pyrotinib to the neoadjuvant treatment of HER2-positive breast cancer patients with a poor response to initial docetaxel plus carboplatin and trastuzumab (TCbH). Early response was assessed using magnetic resonance imaging (MRI) after two cycles of treatment. Patients showing poor response, as defined by RECIST 1.1, could opt to receive additional pyrotinib or continue standard therapy. The primary endpoint was the total pathological complete response (tpCR; ypT0/isN0) rate. Of the 129 patients enroled, 62 (48.1%) were identified as MRI-responders (cohort A), 26 non-responders continued with four more cycles of TCbH (cohort B), and 41 non-responders received additional pyrotinib (cohort C). The tpCR rate was 30.6% (95% CI: 20.6–43.0%) in cohort A, 15.4% (95% CI: 6.2–33.5%) in cohort B, and 29.3% (95% CI: 17.6–44.5%) in cohort C. Multivariable logistic regression analyses demonstrated comparable odds of achieving tpCR between cohorts A and C (odds ratio = 1.04, 95% CI: 0.40–2.70). No new adverse events were observed with the addition of pyrotinib. Patients with co-mutations of TP53 and PIK3CA exhibited lower rates of early partial response compared to those without or with a single gene mutation (36.0% vs. 60.0%, P = 0.08). These findings suggest that adding pyrotinib may benefit patients who do not respond to neoadjuvant trastuzumab plus chemotherapy. Further investigation is warranted to identify biomarkers predicting patients’ benefit from the addition of pyrotinib.

Emerging evidence demonstrates that cryptic translation from RNAs previously annotated as noncoding might generate microproteins with oncogenic functions. However, the importance and underlying mechanisms of these microproteins in alternative splicing-driven tumor progression have rarely been studied. Here, we show that the novel protein TPM3P9, encoded by the lncRNA tropomyosin 3 pseudogene 9, exhibits oncogenic activity in clear cell renal cell carcinoma (ccRCC) by enhancing oncogenic RNA splicing. Overexpression of TPM3P9 promotes cell proliferation and tumor growth. Mechanistically, TPM3P9 binds to the RRM1 domain of the splicing factor RBM4 to inhibit RBM4-mediated exon skipping in the transcription factor TCF7L2. This results in increased expression of the oncogenic splice variant TCF7L2-L, which activates NF-κB signaling via its interaction with SAM68 to transcriptionally induce RELB expression. From a clinical perspective, TPM3P9 expression is upregulated in cancer tissues and is significantly correlated with the expression of TCF7L2-L and RELB. High TPM3P9 expression or low RBM4 expression is associated with poor survival in patients with ccRCC. Collectively, our findings functionally and clinically characterize the “noncoding RNA”-derived microprotein TPM3P9 and thus identify potential prognostic and therapeutic factors in renal cancer.

The newly emerged variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) demonstrate resistance to present therapeutic antibodies as well as the capability to evade vaccination-elicited antibodies. JN.1 sublineages were demonstrated as one of the most immune-evasive variants, showing higher neutralization resistance compared to XBB.1.5. In this study, serum samples were collected from adult participants including those who had gone through the BA.5/BF.7, EG.5/HK.3 and XBB/JN.1 infection waves, characterized by different infection and vaccination histories. We evaluated the neutralization in these serum samples against pseudoviruses of Omicron lineages. We further investigated humoral immune response of recombinant XBB vaccines against Omicron variants and estimated the neutralization resistance of JN.1 sublineages, including KP.2 and KP.3. Our results showed that sera from previous circulating Omicron subvariant breakthrough infections exhibited low neutralization against pseudoviruses of Omicron lineages. The GMTs of 50% neutralization against all tested pseudoviruses were significantly elevated in sera from individuals who received WSK-V102C or WSK-V102D boosters. Importantly, the GMTs of 50% neutralization in serum samples from individuals 4 months after a WSK-V102D booster against XBB.1.5, JN.1, JN.1.13, KP.2 and KP.3 pseudoviruses were 3479, 1684, 1397, 1247 and 1298, with 9.86-, 9.79-, 8.73-, 8.66- and 8.16-fold increase compared to those without booster, respectively, indicating that boosting with XBB.1.5 subunit vaccines still induced strong antibody responses against JN.1 sublineages. However, JN.1 sublineages, including KP.2 and KP.3, revealed more than 2-fold decreases in neutralizing antibody titers compared to XBB.1.5, suggesting significantly enhanced neutralization evasion and the necessity of boosters based on JN.1, KP.2 or KP.3.

CD8⁺T cells within the tumor microenvironment (TME) are often functionally impaired, which limits their ability to mount effective anti-tumor responses. However, the molecular mechanisms behind this dysfunction remain incompletely understood. Here, we identified valosin-containing protein (VCP) as a key regulator of CD8⁺T cells suppression in hepatocellular carcinoma (HCC). Our findings reveal that VCP suppresses the activation, expansion, and cytotoxic capacity of CD8⁺T cells both in vitro and in vivo, significantly contributing to the immunosuppressive nature of the TME. Mechanistically, VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), leading to the accumulation of glycerol-3-phosphate (G3P), a downstream metabolite of GPD1L. The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK, a critical component of the T-cell receptor (TCR) signaling pathway in CD8⁺T cells. This interaction heightens the phosphorylation of Tyr505, a key inhibitory residue, ultimately reducing LCK activity and impairing downstream TCR signaling. Consequently, CD8⁺T cells lose their functional capacity, diminishing their ability to fight against HCC. Importantly, we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8⁺T cells, suggesting synergistic therapeutic potential. These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME, positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.

In a recent study published in Nature Medicine, Wang, Shao, and colleagues successfully addressed two critical issues of lung cancer (LC) screening with low-dose computed tomography (LDCT) whose widespread implementation, despite its capacity to decrease LC mortality, remains challenging: (1) the difficulty in accurately distinguishing malignant nodules from the far more common benign nodules detected on LDCT, and (2) the insufficient coverage of LC screening in resource-limited areas.¹

Human papillomaviruses, particularly high-risk human papillomaviruses, have been universally considered to be associated with the oncogenesis and progression of various cancers. The genome of human papillomaviruses is circular, double-stranded DNA that encodes early and late proteins. Each of the proteins is of crucial significance in infecting the epithelium of host cells persistently and supporting viral genome integrating into host cells. Notably, E6 and E7 proteins, classified as oncoproteins, trigger the incidence of cancers by fostering cell proliferation, hindering apoptosis, evading immune surveillance, promoting cell invasion, and disrupting the balance of cellular metabolism. Therefore, targeting human papillomaviruses and decoding molecular mechanisms by which human papillomaviruses drive carcinogenesis are of great necessity to better treat human papillomaviruses-related cancers. Human papillomaviruses have been applied clinically to different facets of human papillomavirus-related cancers, including prevention, screening, diagnosis, treatment, and prognosis. Several types of prophylactic vaccines have been publicly utilized worldwide and have greatly decreased the occurrence of human papillomavirus-related cancers, which have benefited numerous people. Although various therapeutic vaccines have been developed and tested clinically, none of them have been officially approved to date. Enhancing the efficacy of vaccines and searching for innovative technologies targeting human papillomaviruses remain critical challenges that warrant continuous research and attention in the future.