Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Low-Cost Photoelectric Flow Rate Sensors Based on a Flexible Planar Curved Beam Structure for Clinical Treatments.

In clinical treatments, reliable flow rate measurements ensure accurate drug delivery during infusions, precise gas delivery during artificial ventilations, etc., thereby reducing patient morbidity and mortality. However, precise flow rate sensors are costly, so medical devices with limited budgets choose cheaper but unsatisfactory flow rate measurement approaches, leading to increased medical risks. Here, a photoelectric flow rate sensor based on a flexible planar curved beam structure (FPCBS) is proposed. The FPCBS ensures low out-of-plane stiffness of the sensitive sheet and allows large deformation in the elastic range, enabling the flow rate sensor to measure the flow rate with high sensitivity over a wide range. Meanwhile, the flow rate sensor can be mass-produced using mature materials and manufacturing technology at less than $5 each. The flow rate sensors are integrated into a commercial infusion pump to measure drug infusion and a home ventilator to monitor respiration. The results are comparable to those measured by a commercial flow rate sensor, demonstrating the applicability of the sensor. Considering its proven outstanding performance at low cost, the flow rate sensor shows great potential in clinical treatment, medical diagnosis, and other medical fields.

Identification of New EGFR Inhibitors by Structure-Based Virtual Screening and Biological Evaluation.

Epidermal growth factor receptor (EGFR) inhibitors have been used in clinical for the treatment of non-small-cell lung cancer for years. However, the emergence of drug resistance continues to be a major problem. To identify potential inhibitors, molecular docking-based virtual screening was conducted on ChemDiv and Enamine commercial databases using the Glide program. After multi-step VS and visual inspection, a total of 23 compounds with novel and varied structures were selected, and the predicted ADMET properties were within the satisfactory range. Further molecular dynamics simulations revealed that the reprehensive compound ZINC49691377 formed a stable complex with the allosteric pocket of EGFR and exhibited conserved hydrogen bond interactions with Lys 745 and Asp855 of EGFR over the course of simulation. All compounds were further tested in experiments. Among them, the most promising hit ZINC49691377 demonstrated excellent anti-proliferation activity against H1975 and PC-9 cells, while showing no significant anti-proliferation activity against A549 cells. Meanwhile, apoptosis analysis indicated that the compound ZINC49691377 can effectively induce apoptosis of H1975 and PC-9 cells in a dose-dependent manner, while having no significant effect on the apoptosis of A549 cells. The results indicate that ZINC49691377 exhibits good selectivity. Based on virtual screening and bioassays, ZINC4961377 can be considered as an excellent starting point for the development of new EGFR inhibitors.

Effects of measurement protocols and repetitions on handgrip strength weakness and asymmetry in patients with cancer.

BACKGROUND: The use of handgrip strength (HGS) in clinical cancer research is surging. The association between HGS and outcomes in patients with cancer varied across studies, which might be due to the different measurement protocols for HGS. We aimed to answer three questions: (1) Did the use of various protocols for HGS, along with different numbers of repetitions, lead to significant differences in maximum HGS values? (2) If yes, were these differences clinically significant? (3) Did the differences in HGS protocols and repetitions affect the identification of HGS weakness or HGS asymmetry? METHODS: We continuously recruited adult patients with solid tumours. Two protocols were used to measure HGS: Method A, following the American Society of Hand Therapists guidelines, and Method B, following the National Health and Nutrition Examination Survey guidelines. To analyse HGS, we used the maximal value obtained from either two or three repetitions of the dominant hand or four or six repetitions of both hands. RESULTS: We included 497 patients (326 men and 171 women, median age: 58 years). The maximal HGS values, measured with Method B, were significantly higher than those measured by Method A in both men and women, despite repetitions (all P < 0.05). The maximum HGS values were significantly different across the repetition groups, regardless of measurement protocols and sex (all P < 0.01). The protocol-induced differences in maximal HGS values might be clinically meaningful in over 60% of men and 40% of women despite repetitions. The repetition-induced difference was only clinically significant in 4.3-17.8% of men and 4.1-14.6% of women. To identify HGS weakness, using Method A (six repetitions) as the 'gold' standard, the other protocols demonstrated an overall accuracy of 0.923-0.997 in men and 0.965-1 in women. To identify HGS asymmetry, using Method A (six repetitions) as the 'gold' standard, Method B (six repetitions) demonstrated a diagnostic accuracy of 0.972 in men and 0.971 in women. Method A (four repetitions) showed a diagnostic accuracy of 0.837 in men and 0.825 in women, while Method B (four repetitions) showed a diagnostic accuracy of 0.825 in men and 0.807 in women. CONCLUSIONS: Both measurement protocols and repetitions significantly affect the maximal HGS values. The identification of HGS weakness is not significantly affected by either protocols or repetitions, while the identification of HGS asymmetry may be affected by different repetitions but not protocols.

The Progress of Research on Genetic Factors of Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is both mental and physical health problem affecting about 1-5% of women of childbearing age. The etiology of RPL is complex, involving chromosomal abnormalities, autoimmune diseases, metabolic disorders, and endometrial dysfunction. The causes of abortion are still unknown in more than 50% of these cases. With the development of science and technology, an increasing number of scholars focus on this field and find that genetic factors may play an essential role in unexplained RPL, such as embolism-related genes, immune factor-related genes, and chromosomal numeric, and structural variation. This review summarizes the genetic factors associated with RPL, including genetic mutations and genetic polymorphisms, chromosomal variants, and chromosomal polymorphisms. Many related genetic factors have been found to be demographically and geographically relevant, some of which can be used for risk prediction or screening for the etiology of RPL. However, it is difficult to predict and prevent RPL due to uncertain pathogenesis and highly variable clinical presentation. Therefore, the genetic factors of RPL still need plentiful research to obtain a more accurate understanding of its pathogenesis and to provide more detection means for the screening and prevention of RPL.

The multi-molecular mechanisms of tumor-targeted drug resistance in precision medicine.

Clinically, cancer drug therapy is still dominated by chemotherapy drugs. Although the emergence of targeted drugs has greatly improved the survival rate of patients with advanced cancer, drug resistance has always been a difficult problem in clinical cancer treatment. At the current level of medicine, most drugs cannot escape the fate of drug resistance. With the emergence and development of gene detection, liquid biopsy ctDNA technology, and single-cell sequencing technology, the molecular mechanism of tumor drug resistance has gradually emerged. Drugs can also be updated in response to drug resistance mechanisms and bring higher survival benefits. The use of new drugs often leads to new mechanisms of resistance. In this review, the multi-molecular mechanisms of drug resistance are introduced, and the overcoming of drug resistance is discussed from the perspective of the tumor microenvironment.

Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686.

Epidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFRL858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-9 (EGFRDel 19) and H1975 (EGFRL858R/T790M) cells, but not that of A549 (EGFRWT) cells. In addition, 1q could time- and dose-dependently induce degradation of EGFRL858R/T790M in H1975 cells with a DC50 value of 355.9 nM, while did not show obvious effect on the EGFRDel 19 and EGFRWT protein. Preliminary mechanism study demonstrated that the protein degradation was mediated through ubiquitin-proteasome system (UPS). Furthermore, 1q could significantly induce the apoptosis of H1975 cells and arrest the cells in G0/G1 phase. These findings demonstrated that compound 1q could be used as initial lead compound for the development of new EGFRL858R/T790M degraders based therapy.

Molecular mechanism study of EGFR allosteric inhibitors using molecular dynamics simulations and free energy calculations.

ABTRACTThe epidermal growth factor receptor (EGFR) kinase inhibitors Gefitinib, Erlotinib, Afatinib and Osimertinib have been approved for the treatments of non-small cell lung cancer patients harboring sensitive EGFR mutations, but resistance arises rapidly. To date all approved EGFR inhibitors are ATP-competitive inhibitors, highlighting the need for therapeutic agents with alternative mechanisms of action. Allosteric kinase inhibitors offer a promising new therapeutic strategy to ATP-competitive inhibitors. The mutant-selective allosteric EGFR inhibitors EAI045 exhibited higher potency for EGFRL858R&T790M compared to WT, which was also effective in EGFR-mutant models including those harboring the C797S mutation. However, it was not effective as a single-agent inhibitor, and require the co-administration of the anti-EGFR antibody Cetuximab. Further efforts produced a more potent analog JBJ-04-125-02, which can inhibit cell proliferation as a single-agent inhibitor. In the present study, molecular dynamics simulations and free energy calculations were performed and revealed the detailed inhibitory mechanism of JBJ-04-125-02 as more potent EGFR inhibitor. Moreover, the energy difference between HOMO and LUMO calculated by DFT implied the higher interaction of JBJ-04-125-02 than EAI045 in the active site of the EGFR. The identified key features obtained from the molecular modeling enabled us to design novel EGFR allosteric inhibitors.Communicated by Ramaswamy H. Sarma.

Contact-Resistance-Free Stretchable Strain Sensors with High Repeatability and Linearity.

Most of the existing stretchable strain sensors are based on the contact-resistance mechanism, where the stretchability and resistance variation depend on the change of the contact relationship of the conductive microstructures. These sensors usually exhibit large sensing ranges and gauge factors but unsatisfactory repeatability and linearity of the electrical responses because the contact is unstable. Here, we report a completely different design for stretchable strain sensors based on a contact-resistance-free structure, i.e., the off-axis serpentine sandwich structure (OASSS), with the mechanism of the stretch-bending-stretch transformation (SBST). Neither unstable contact resistance nor nonlinear constitutive and geometric behaviors occur for the OASSS while the sensor undergoes a large applied strain (50%), which guarantees high repeatability (repeatability error = 1.58%) and linearity (goodness-of-fit >0.999). Owing to such performances, the present sensors are not only applied to monitoring human activities and medical surgery but also to the ground tests of Tianwen-1, China's first Mars exploration mission.

Molecular dynamics simulation and free energy calculation studies of the binding mechanism of allosteric inhibitors with TrkA kinase.

Tropomyosin receptor kinase A (Trk A) is a receptor tyrosine kinase activated by nerve growth factor (NGF). TrkA plays an important role in pain sensation, which leads to significant interest in the development of small molecule inhibitors of TrkA. However, TrkA and the other two highly homologous isoforms, TrkB and TrkC, are highly conserved in the ATP binding site, which suggests that achieving TrkA subtype selectivity over TrkB and TrkC in this site may be extremely challenging. Allosteric inhibitors without making any interactions with the conserved ATP binding site may present a more promising approach. Recently, selective TrkA inhibitors 1 and 2 were reported to be allosteric inhibitors targeting the DFG-out allosteric pocket. In the present study, molecular dynamics simulations and free energy calculations were carried out on TrkA in complex with ligands 1 and 2, which was expected to provide a basis for the rational drug design of TrkA allosteric inhibitors.