High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by an immunosuppressive tumor microenvironment containing few tumor infiltrating lymphocytes (TILs) and an insensitivity ...to checkpoint inhibitor immunotherapies. Gains in the PTK2 gene encoding focal adhesion kinase (FAK) at Chr8 q24.3 occur in ∼70% of HGSOC tumors, and elevated FAK messenger RNA (mRNA) levels are associated with poor patient survival. Herein, we show that active FAK, phosphorylated at tyrosine-576 within catalytic domain, is significantly increased in late-stage HGSOC tumors. Active FAK costained with CD155, a checkpoint receptor ligand for TIGIT (T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains), in HGSOC tumors and a selective association between FAK and TIGIT checkpoint ligands were supported by patient transcriptomic database analysis. HGSOC tumors with high FAK expression were associated with low CD3 mRNA levels. Accordingly, late-stage tumors showed elevated active FAK staining and significantly lower levels of CD3+ TILs. Using the KMF (Kras, Myc, FAK) syngeneic ovarian tumor model containing spontaneous PTK2 (FAK) gene gains, the effects of tumor intrinsic genetic or oral small molecule FAK inhibitior (FAKi; VS-4718) were evaluated in vivo. Blocking FAK activity decreased tumor burden, suppressed ascites KMF-associated CD155 levels, and increased peritoneal TILs. The combination of FAKi with blocking TIGIT antibody (1B4) maintained elevated TIL levels and reduced TIGIT+ T regulatory cell levels, prolonged host survival, increased CXCL13 levels, and led to the formation of omental tertiary lymphoid structures. Collectively, our studies support FAK and TIGIT targeting as a rationale immunotherapy combination for HGSOC.
Simulation of metal cutting by Finite Element Method largely depends on material model and friction model. Inconel 625 is one of the super alloys, which has numerous applications but has no specific ...material model and friction model for simulating metal cutting. The Inconel 625 has a behaviour of softening at higher strain and strain rates. Material models that are already available do not represent this behaviour of Inconel 625. This paper follows the modified Johnson-Cook material model suggested by Hokka to obtain the flow stress data. Parameters like Cutting force, Temperature at tool chip interface, Tool Wear can be used to evaluate the effectiveness of friction model by comparing those obtained experimentally with the simulation results. In this paper, the Cutting forces are considered for evaluation of friction model. Cutting forces obtained experimentally by the turning of Inconel 625 rod with TiN tool insert. Simulation of the turning of Inconel 625 is done in DEFORM 3D software. Coulomb Friction model and Shear Friction model are the two friction models taken for investigation in this paper. Simulation is carried out by applying the two friction models and the actual process parameters. On comparison with the experimental results, Shear Friction model is found to be more accurate than the coulomb friction model for Inconel 625.
Serine/threonine protein kinases (STPK) play a major role in the physiology and pathogenesis of
Mycobacterium tuberculosis
. Here, we have examined the role of
pknE
, a STPK in the adaptive responses ...of
M. tuberculosis
using a deletion mutant
ΔpknE
. The survival of
ΔpknE
was assessed in the presence of stress (pH, surfactant and cell wall–damaging agents) and anti-tuberculosis drugs.
ΔpknE
had a defective growth in pH 7.0 and lysozyme (a cell wall–damaging agent) with better survival in pH 5.5, SDS and kanamycin (a second-line anti-tuberculosis drug). Furthermore,
ΔpknE
was reduced in cell size during growth in liquid media and exhibited hypervirulence in a guinea pig model of infection. In conclusion, our data suggest that
pknE
plays a role in adaptive response of
M. tuberculosis
regulating cellular integrity and survival.
In this study, we typed 51 male individuals from North Borneo using 17 Y-chromosome STRs contained in the AmpFLSTR® Yfiler® kit (Applied Biosystems). These individuals constitute five indigenous ...ethnic populations representing the three major linguistic groups (Dusunic, Murutic and Paitanic): the Dusun (n=7), Rungus (n=12), Sonsogon (n=12), Murut Paluan (n=12), and Sungai Lingkabau Paitan (n=8). A total of 37 haplotypes were identified, of which 30 individuals were represented by a single haplotype. The mean ± S.D. haplotype diversity was 0.600±0.181 and the discrimination capacity was 0.725. The results also showed that the haplotype H33 was the most frequent haplotype observed in the sampled male populations occurring exclusively in the Murut population. Comparative analysis between Y-haplotype populations of North Borneo and the ethnic populations (Bidayuh, Iban, and Melanau) of neighbouring Sarawak (East Malaysia) i.e. indicated that the Sungai Lingkabau Paitan was more closely associated with the Melanau with respect to Y-haplotype descent (RST=- 0.0023). In addition, the Multidimensional Scaling (MSD) analysis managed to clearly differentiate the eight groups from Borneo. We concluded that the 17 Y-chromosome STRs data of North Bornean populations are valuable resources in the applications of forensic and population genetics of the ethnic groups.
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