The novel HLA-C*12:392 allele was identified in four unrelated bone marrow donors.

One nucleotide substitution in codon 83 of HLA-С*12:02:02:01 results in the novel allele, HLA-C*12:392.

The novel HLA-A*74:46 allele detected in a potential hematopoietic stem cell donor.

One nucleotide substitution in codon 67 of HLA-A*74:41 results in the novel allele, HLA-A*74:46.

Identification of three novel HLA-A*24 alleles by next generation sequencing.

Three novel A*24:614, A*24:615, and A*24:616 alleles detected in a potential hematopoietic stem cell donors.

Recognition of the novel HLA-A*24:602 allele detected in a potential hematopoietic stem cell donor.

The novel HLA-A*24:602 allele differs by one nucleotide change from HLA-A*24:02:01:01.

Characterization of the novel HLA-C*07:402:02 allele detected in a potential hematopoietic stem cell donor.

The novel HLA-C*07:402:02 allele was characterized using next-generation sequencing technology.

Unraveling the Mechanisms of Sensitivity to Anti-FGF Therapies in Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Lacking Secondary KIT Mutations.

We showed previously that inhibition of KIT signaling in GISTs activates FGFR-signaling pathway rendering cancer cells resistant to receptor tyrosine kinase inhibitor (RTKi) imatinib mesylate (IM) (Gleevec) despite of absence of secondary KIT mutations and thereby illustrating a rationale for the combined (e.g., KIT- and FGFR-targeted) therapies. We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398's activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway).

Predictive risk factors before the onset of familial rheumatoid arthritis: the Tatarstan cohort study.

Background: A familial history of rheumatoid arthritis (RA) predisposes an individual to develop RA. This study aimed at investigating factors associated with this conversion from the Tatarstan cohort. Methods: A total of 144 individuals, referred to as pre-RA and at risk for familial RA, were selected 2 years (range: 2-21 years) before conversion to RA and compared to non-converted 328 first-degree relatives (FDR) from RA as assessed after ≥2 years follow-up, and 355 healthy controls were also selected (HC). Preclinical parameters and socio-demographic/individual/HLA genetic factors were analyzed when data were available at the time of enrollment. Results: As compared to FDR and HC groups, pre-RA individuals were characterized before conversion to RA by the presence of arthralgia, severe morning symptoms, a lower educational level, and rural location. An association with the HLA-DRB1 SE risk factor was also retrieved with symmetrical arthralgia and passive smoking. On the contrary, alcohol consumption and childlessness in women were protective and associated with the HLA-DRB1*07:01 locus. Conclusion: Before RA onset, a combination of individual and genetic factors characterized those who are at risk of progressing to RA among those with familial RA relatives.

Population Genomics of Two Closely Related Anhydrobiotic Midges Reveals Differences in Adaptation to Extreme Desiccation.

The sleeping chironomid Polypedilum vanderplanki is capable of anhydrobiosis, a striking example of adaptation to extreme desiccation. Tolerance to complete desiccation in this species is associated with emergence of multiple paralogs of protective genes. One of the gene families highly expressed under anhydrobiosis and involved in this process is protein-L-isoaspartate (D-aspartate) O-methyltransferases (PIMTs). Recently, another closely related midge was discovered, Polypedilum pembai, which is able not only to tolerate desiccation but also to survive multiple desiccation-rehydration cycles. To investigate the evolution of anhydrobiosis in these species, we sequenced and assembled the genome of P. pembai and compared it with P. vanderplanki and also performed a population genomics analysis of several populations of P. vanderplanki and one population of P. pembai. We observe positive selection and radical changes in the genetic architecture of the PIMT locus between the two species, including its amplification in the P. pembai lineage. In particular, PIMT-4, the most highly expressed of these PIMTs, is present in six copies in the P. pembai; these copies differ in expression profiles, suggesting possible sub- or neofunctionalization. The nucleotide diversity of the genomic region carrying these new genes is decreased in P. pembai, but not in the orthologous region carrying the ancestral gene in P. vanderplanki, providing evidence for a selective sweep associated with postduplication adaptation in the former. Overall, our results suggest an extensive relatively recent and likely ongoing adaptation of the mechanisms of anhydrobiosis.

The Spectrum of Germline Nucleotide Variants in Gastric Cancer Patients in the Kyrgyz Republic.

Gastric cancer is a major challenge in modern oncology due to its high detection rate and prevalence. While sporadic cases make up the majority of gastric cancer, hereditary gastric cancer is caused by germline mutations in several genes linked to different syndromes. Thus, identifying hereditary forms of gastric cancer is considered crucial globally. A survey study using NGS-based analysis was conducted to determine the frequency of different types of hereditary gastric cancer in the yet-unstudied Kyrgyz population. The study cohort included 113 patients with diagnosed gastric cancer from Kyrgyzstan. The age of patients was 57.6 ± 8.9. Next-generation sequencing analysis of genomic DNA was performed using a custom Roche NimbleGen enrichment panel. The results showed that 6.2% (7/113) of the patients had pathogenic or likely pathogenic genetic variants. Additionally, 3.5% (4/113) of the patients carried heterozygous pathogenic/likely pathogenic variants in high penetrance genes, such as TP53, POLD1, RET, and BRCA2. Moreover, 2.7% (3/113) of the patients carried heterozygous mutations in genes linked to autosomal recessive conditions, specifically PALB2, FANCA, and FANCD2. We have not identified any genetic variants in hereditary GC-associated genes: CDH1, STK11, SMAD4, BMPRIA, APC, MLH1, and others. Our study included patients with sporadic features of GC. The use of recognized criteria (NCCN, Gastric Cancer, Version 2.2022) would increase the number of identified genetic variants in hereditary GC-associated genes. Further research is required to determine the clinical relevance of the genetic variants identified in the current study.

Characterization of the novel HLA-B*27:05:57 allele detected in a potential hematopoietic stem cell donor.

The novel HLA-B*27:05:57 allele differs by two nucleotide changes from HLA-B*27:05:02:01.

Characterization of the novel HLA-A*03:444 detected in a potential hematopoietic stem cell donor.

The novel HLA-A*03:444 allele was characterized using next generation sequencing technology.

Identification of the novel HLA-C*12:349 allele in a potential hematopoietic stem cell donor.

The novel HLA-C*12:349 allele was characterized using next generation sequencing technology.

The novel HLA-A*03 allele, HLA-A*03:440, identified in a potential hematopoietic stem cell donor.

The novel HLA-A*03:440 allele was characterized using next generation sequencing technology.

Identification of the novel HLA-B*07:458 allele, detected in two unrelated bone marrow donors.

HLA-B*07:458 has one non-synonymous nucleotide compared with HLA-B*07:02:01 in codon-21.

Identification of the novel HLA-C*02:212 allele detected in a potential hematopoietic stem cell donor.

The novel HLA-C*02:212 allele was characterized using next generation sequencing technology.

The novel HLA-C*04:441:01:02 allele was identified in three unrelated bone marrow donors.

The novel HLA-C*04:441:01:02 allele was characterized using next generation sequencing technology.

Recognition of the novel HLA-C*07:1002 allele identified in a potential hematopoietic stem cell donor.

The novel HLA-C*07:1002 allele was characterized using next-generation sequencing technology.

The novel HLA-A*02:1009 allele was identified in four unrelated bone marrow donors.

HLA-A*02:1009 has one non-synonymous nucleotide change from A*02:01:01:01 at codon 320.

Characterization of the novel HLA-B*35:547 allele detected in a potential hematopoietic stem cell donor.

The novel HLA-B*35:547 allele was characterized using next generation sequencing technology.

The detection of the novel HLA-C*04:469 allele identified in a potential hematopoietic stem cell donor.

The novel HLA-C*04:469 allele was characterized using next generation sequencing technology.