The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by ...which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.
Purpose
To develop a selective micropulse individual retinal therapy (SMIRT) based on the age and appearance type of the patient, to derive a formula for calculating power, and evaluate clinical ...efficacy for the treatment of central serous chorioretinopathy (CSCR).
Methods
73 patients (aged 30–65 years) with acute CSCR and types 1–4 on the Fitzpatrick scale were divided into 2 groups. In the first group (33 patients), the testing of the micropulse mode (50 µs, 2.4%, 10 ms, 100 µm, 0.4–1.9 W) on the Navilas 577 s laser system defined as selective by computer modeling was performed. A logistic regression function based on probability damage detection (PDD) of the 1584 laser spots from power, age, and type on the Fitzpatrick scale was constructed. PDD is the probability of detecting the laser spots using the autofluorescence method. The second group was divided into 4 subgroups of 10 eyes each. Groups 2.1, 2.2, and 2.3 were treated without preliminary testing. The power for Groups 2.1, 2.2, and 2.3 was obtained with the inverse PDD function, so that PDD was 50%, 70%, and 90%, respectively. Control group 2.4 went without treatment.
Results
The transmission and absorption coefficients of laser radiation of the eye depend on the age and the Fitzpatrick scale type. In Groups 2.1–2.3, complete resorption of subretinal fluid was observed 3 months after CSCR treatment in 5 (
P
< 0.35), 8 (
P
< 0.023), and 10 eyes (
P
< 0.0008) out of 10, respectively.
Conclusion
The developed SMIRT is effective for CSCR treatment with PDD 90%.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for
-mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired ...drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in
-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: EGFR inhibition leads to increased HER3 membrane expression and promotes HER3-DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer.
.
Despite the success of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget RAS and mTOR pathways; however, ...toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identifying the most therapeutically important eukaryotic initiation factor 4F complex-translated (eIF4F-translated) targets. Here, we show that an eIF4A inhibitor, which targets a component of eIF4F, dramatically enhances the effects of KRAS G12C inhibitors in NSCLCs and together these agents induce potent tumor regression in vivo. By screening a broad panel of eIF4F targets, we show that this cooperativity is driven by effects on BCL-2 family proteins. Moreover, because multiple BCL-2 family members are concomitantly suppressed, these agents are broadly efficacious in NSCLCs, irrespective of their dependency on MCL1, BCL-xL, or BCL-2, which is known to be heterogeneous. Finally, we show that MYC overexpression confers sensitivity to this combination because it creates a dependency on eIF4A for BCL-2 family protein expression. Together, these studies identify a promising therapeutic strategy for KRAS-mutant NSCLCs, demonstrate that BCL-2 proteins are the key mediators of the therapeutic response in this tumor type, and uncover a predictive biomarker of sensitivity.
The
proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly ...selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating
gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood.
We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have
amplification associated with resistance to selpercatinib. We validated
activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP).
amplification was identified in posttreatment biopsies in 4 patients with
fusion-positive NSCLC treated with selpercatinib. In at least one case,
amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in
fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months.
Through the use of SPPs, we were able to offer combination therapy targeting
-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
A general method for ring opening of various donor–acceptor cyclopropanes with the azide ion through an SN2‐like reaction has been developed. This highly regioselective and stereospecific process ...proceeds through nucleophilic attack on the more‐substituted C2 atom of a cyclopropane with complete inversion of configuration at this center. Results of DFT calculations support the SN2 mechanism and demonstrate good qualitative correlation between the relative experimental reactivity of cyclopropanes and the calculated energy barriers. The reaction provides a straightforward approach to a variety of polyfunctional azides in up to 91 % yield. The high synthetic utility of these azides and the possibilities of their involvement in diversity‐oriented synthesis were demonstrated by the developed multipath strategy of their transformations into five‐, six‐, and seven‐membered N‐heterocycles, as well as complex annulated compounds, including natural products and medicines such as (−)‐nicotine and atorvastatin.
A new world of opportunities: Stereospecific ring opening of donor–acceptor cyclopropanes with the azide ion gives rise to densely functionalized building blocks that are valuable for the assembly of a diverse range of N‐heterocycles (see scheme; EDG=electron donating group; EWG=electron withdrawing group). These synthetic opportunities are provided by the simultaneous presence of the N3 group, which reacts as a latent amine or 1,3‐dipole, easily modifiable donor and acceptor substituents, as well as the activated CH fragment.
To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX).
In this 24-week multicentre, placebo-controlled, ...double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study.
A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies.
Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed.
NCT02760368.
A combination of a high sediment input and intense bottom currents often leads to the formation of contourites (sediments deposited or significantly reworked by bottom currents). Both of these ...components are present in the Vema Fracture Zone valley which is the most important passageway for the distribution of the Antarctic Bottom Water from the West to the North-East of the Atlantic. However, no contourite drifts, moats or contourite channels have been found in this region in more than half a century of research. The prevailing sedimentation paradigm postulates that turbidity currents have predominantly governed sedimentation in this region during the Pleistocene. This work describes the first example of contourite depositional system identified in the Vema Fracture Zone. The discovery was made through detailed high-resolution sub-bottom profiling, as well as numerical modeling and direct measurements of bottom current velocities. Such systems are exceptionally uncommon in fracture zones. This study highlights the importance of further research of contourites along the Vema Fracture Zone based on modern concepts of contourite and mixed depositional systems. The work also emphasizes the need to reevaluate the impact of bottom currents on sedimentation in this region, and particularly in the narrow segments of the fracture zone valley.
In this study, we determined the levels of cytokine secretory inhibitors and the microbiota biofilms of semen from healthy and infertile subjects. A total of 118 clinical bacterial isolates were ...isolated and tested. Cytokine secretory inhibitors were determined based on the difference in cytokine content between the control and experimental samples of cell-free supernatants of isolated microorganisms. Biofilm formation was studied by determining the adhesion of microorganisms to the surface of a 96-well sterile plate and expressed as the optical density at 630 nm (OD630). Cell-free supernatants of Staphylococcus contained higher levels of secretory inhibitor of cytokines in conditionally healthy than in infertile patients. In contrast, in infertile men, the ability to reduce cytokine levels was more characteristic of Enterococcus and Corynebacterium. Seminal Staphylococcus, Corynebacterium, and Enterococcus isolated from infertile subjects showed a greater ability to form biofilms than the same bacteria isolated from healthy men. Further research is needed on this topic, since it is necessary to determine the relationships between decreased secretory inhibitors of cytokines, production of biofilms by bacteria in semen, and infertility. It is likely that the ability of microorganisms to change the concentration of cytokines and increase the level of biofilm formation in semen may be associated with minimal impairments of fertilizing ability, which are not detected using other methods.
A long-standing hypothesis on tumorigenesis is that cell division failure, generating genetically unstable tetraploid cells, facilitates the development of aneuploid malignancies. Here we test this ...idea by transiently blocking cytokinesis in p53-null (p53-/-) mouse mammary epithelial cells (MMECs), enabling the isolation of diploid and tetraploid cultures. The tetraploid cells had an increase in the frequency of whole-chromosome mis-segregation and chromosomal rearrangements. Only the tetraploid cells were transformed in vitro after exposure to a carcinogen. Furthermore, in the absence of carcinogen, only the tetraploid cells gave rise to malignant mammary epithelial cancers when transplanted subcutaneously into nude mice. These tumours all contained numerous non-reciprocal translocations and an 8-30-fold amplification of a chromosomal region containing a cluster of matrix metalloproteinase (MMP) genes. MMP overexpression is linked to mammary tumours in humans and animal models. Thus, tetraploidy enhances the frequency of chromosomal alterations and promotes tumour development in p53-/- MMECs.
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