nts with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
Genetic faults in several components of the nuclear factor-κB pathway cause immunodeficiency. Most defects lead to combined immunodeficiency with a range of severity. Heterozygous mutations in NFKB1 were associated with common variable immunodeficiency, however, homozygous mutations have not been described.
We studied the molecular basis of combined immunodeficiency in a patient who presented with failure to thrive, persistent EBV viremia and hepatitis, pneumocystis jirovecii pneumonitis, and generalized lymphadenopathy.
Whole genome and exome sequencing followed by Sanger confirmation were performed to identify the genetic defect. Molecular and cellular techniques were used to assess the variant impact on the nuclear factor-κB pathway and lymphocyte function.
Genetic analysis revealed a novel homozygous mutation in NFKB1, c.2878G>A, p.Gly960Arg (G960R). This affected p105 phosphorylation and p50 formation on antigen and cytokine stimulation, as well as attenuating nuclear signal transmission. As a result, both T- and B-cell maturation and function were perturbed. The number of memory CD4
T cells were reduced, while CD8
T cells consisted predominately of expanded differentiated populations. The function of T cells were diminished as shown by reduced responses to mitogens as well as diminished cytokine secretion. B-cell maturation was also affected, with decreased IgD
CD27
memory B cells while transitional B cells were increased, likely contributing to the reduced ability to produce specific antibodies.
Homozygous G960R mutation in NFKB1 leads to a severe clinical presentation of combined immunodeficiency. This was associated with blockade of nuclear factor-κB pathway signaling, resulting in aberrations in T- and B-cell maturation and function.
Homozygous G960R mutation in NFKB1 leads to a severe clinical presentation of combined immunodeficiency. This was associated with blockade of nuclear factor-κB pathway signaling, resulting in aberrations in T- and B-cell maturation and function.NTRK1/3, ALK, and ROS1 translocations have been reported in a minor subset of papillary thyroid carcinomas (PTCs). We aimed to elucidate the prevalence and clinicopathological characteristics of these gene rearrangements and the utility of immunohistochemistry (IHC) in PTC and anaplastic thyroid carcinoma (ATC). We screened nonradiation-exposed cases of 307 PTCs and 16 ATCs by IHC for pan-Trk, ALK, and ROS1, followed by fluorescence in situ hybridization (FISH). In the PTC group, IHC for pan-Trk, ALK, and ROS1 was positive in 18 cases (5.9%), 1 case (0.3%), and 12 cases (3.9%), respectively. GSK-3 inhibitor Among the pan-Trk IHC-positive cases (n = 18), 2 cases (11.1%; 0.7% of all PTCs) had NTRK1 or NTRK3 gene rearrangement with conventional PTC histology. The ALK IHC-positive case (n = 1) was the follicular variant of PTC with consistent ALK gene rearrangement. ROS1 gene rearrangement was not detectable in the ROS1 IHC-positive PTCs (0/12) by FISH. Most (approximately 70%) of the pan-Trk or ROS1 IHC-positive/FISH-negative cases had BRAF gene mutation with conventional PTC morphology. In the ATC group, neither ALK nor ROS1 IHC was positive, whereas pan-Trk IHC was positive in 1 case (6.3%) in which NTRK1 gene rearrangement was confirmed by FISH. These results suggest that NTRK, ALK, and ROS1 rearrangements are rare molecular events in nonradiation-exposed Japanese patients with PTC and ATC. Although IHC is not an entirely specific surrogate for these abnormalities and does not serve as a stand-alone companion diagnosis, the combined use of IHC and molecular testing may be helpful for determining promising therapeutic strategies with tyrosine kinase inhibitors.Conjunctival melanoma (CM) is an ocular malignant tumor arising from the bulbar and palpebral conjunctiva and from the caruncle. The treatment of early-stage CM is wide local excision, followed by cryotherapy to the margins and adjuvant therapy postoperatively. Advanced CM has a poor prognosis, and there is no consensus on its management. With the development of precision medicine, the identification of genetic alterations assumes great importance. The genetic characteristics of CM, such as BRAF, NRAS, and NF1 mutations, may provide potential therapeutic targets. For locally advanced tumors and metastatic disease, targeted therapy such as BRAF inhibitors and MEK inhibitors in vitro show therapeutic benefit. Some individual case reports indicate their potential effectiveness in advanced CM. In addition, immune checkpoint inhibitors, such as programmed cell death-1 and cytotoxic T lymphocyte antigen-4 inhibitors, have been successfully used for advanced cutaneous melanoma and may be effective in CM. Limited clinical case reports found immune checkpoint inhibitors effective in advanced CM. More clinical studies are needed.Perfluorooctanesulfonate (PFOS) is a persistent environmental agent. We examined whether PFOS exposure during pregnancy alters blood pressure in male and female offspring, and if this is related to sex-specific changes in vascular mechanisms. PFOS was administered through drinking water (50 μg/mL) to pregnant Sprague-Dawley rats from gestational day 4 until delivery. PFOS-exposure decreased maternal weight gain but did not significantly alter feed and water intake in dams. The male and female pups born to PFOS mothers were smaller in weight by 29 % and 27 %, respectively. The male PFOS offspring remained smaller through adulthood, but the female PFOS offspring exhibited catch-up growth. The blood pressure at 12 and 16 weeks of age was elevated at similar magnitude in PFOS males and females than controls. Mesenteric arterial relaxation to acetylcholine was reduced in both PFOS males and females, but the extent of decrease was greater in females. Relaxation to sodium-nitroprusside was reduced in PFOS females but unaffected in PFOS males. Vascular eNOS expression was not changed, but phospho(Ser1177)-eNOS was decreased in PFOS males. In PFOS females, both total eNOS and phospho(Ser1177)-eNOS expression were reduced. In conclusion, PFOS exposure during prenatal life (1) caused low birth weight followed by catch-up growth only in females (2) lead to hypertension of similar magnitude in both males and females; (2) decreased endothelium-dependent vascular relaxation in males but suppressed both endothelium-dependent and -independent relaxation in females. The endothelial dysfunction is associated with reduced activity of eNOS in males and decreased expression and activity of eNOS in females.GSK-3 inhibitor
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