Eighth case of Li-Campeau syndrome in a Turkish patient caused by a novel pathogenic variant in UBR7 and expanding the phenotype.

Li-Campeau syndrome (LICAS) is an autosomal recessive disorder characterized by developmental delay, intellectual disability, genital anomalies, congenital heart defects, and dysmorphic features. LICAS is caused by biallelic pathogenic variants in the UBR7 gene, acting as an E3 ubiquitin-protein ligase. Using exome sequencing (ES), we identified a homozygous novel pathogenic splice site variation c.1185+1G>C in UBR7 in a 32-month-old male from a nonconsanguineous Turkish family with clinical features of LICAS. Sanger sequencing revealed the heterozygous state of parents for this variant and confirmed the co-segregation study. The variant may lead to the loss of function of UBR7 and is in a highly conserved residue. Bioinformatic prediction analysis using in silico algorithms supports the pathogenic effect of the splice site variant in the UBR7.

PTPN22 Gene Polymorphisms in Pediatric Systemic Lupus Erythematosus.

Objective: Pediatric systemic lupus erythematosus (PSLE) is a heterogeneous autoimmune disorder of unknown origin. PTPN22 gene polymorphisms have been associated with SLE in different populations. We investigated the associations of the rs2476601, rs1217414, rs33996649, rs1276457, and rs1310182 SNPs in the PTPN22 gene with PSLE. Materials and methods: 55 PSLE patients and 93 healthy controls were recruited. SNPs were genotyped by the real-time PCR allelic discrimination method. Results: We found that the PTPN22 polymorphisms rs1310182 A allele (p = 0.01, OR = 1.92 95% CI = 1.16-3.18), and rs1310182 AA genotype with (p < 0.001) and rs12760457 TT (p = 0.046) were associated with PSLE. No significant associations were found between other SNPs and PSLE. Conclusions: The PTPN22 rs1310182 A allele and rs1310182 AA genotype were associated with PSLE and may be a possible genetic marker for susceptibility to PSLE. However, further investigation would be required to elucidate the mechanistic role of this association.

First Report of Congenital Short Bowel Syndrome in an Iranian Patient Caused by a Mutation in the CLMP Gene.

Congenital short bowel syndrome (CSBS) is a rare congenital neonatal disorder. CSBS results from intestinal impairment during embryogenesis. Mutated CXADR-like membrane protein ( CLMP ) and Filamin A genes are involved in the cause of CSBS. In this study, due to our misdiagnosis, we had to perform whole exome sequencing on the patient, and also we implemented cosegregation analysis on his parents with consanguineous marriage and also parents' mothers. We identified a homozygous loss of function mutation in the CLMP gene in exon 5 (c.664C > T, p.R222X). Also, both parents and grandmothers of the proband were heterozygous for this mutation. Loss of function mutation in CLMP causes CSBS, leading to impaired intestinal development.

Tumor-associated macrophages: role in cancer development and therapeutic implications.

BACKGROUND: Tumor-associated macrophages (TAMs) are known to play important roles in the initiation and progression of human cancers, as well as in angiogenesis. TAMs are considered as main components of the tumor microenvironment. Targeting TAMs may serve as a therapeutic strategy for the treatment of cancer. In this review, the signaling pathways, origin, function, polarization and clinical application of TAMs are discussed. The role of TAMs in tumor initiation, progression, angiogenesis, invasion and metastasis are also emphasized. In addition, a variety of clinical and pre-clinical approaches to target TAMs are discussed. CONCLUSIONS: Clinical therapeutic approaches that show most promise include blocking the extravasation of TAMs along with using TAMs as diagnostic biomarkers for cancer progression. The targeting of TAMs in a variety of clinical settings appears to be a promising strategy for decreasing metastasis formation and for improving patient outcome.

PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy.

Over the course of past few years, cancer immunotherapy has been accompanied with promising results. However, preliminary investigations with respect to immunotherapy concentrated mostly on targeting the immune checkpoints, nowadays, emerge as the most efficient strategy to raise beneficial antitumor immune responses. Programmed cell death protein 1 (PD-1) plays an important role in subsiding immune responses and promoting self-tolerance through suppressing the activity of T cells and promoting differentiation of regulatory T cells. PD-1 is considered as an immune checkpoint and protects against autoimmune responses through both induction of apoptosis in antigen-specific T cells and inhibiting apoptosis in regulatory T cells. Several clinical trials exerting PD-1 monoclonal antibodies as well as other immune-checkpoint blockades have had prosperous outcomes and opened new horizons in tumor immunotherapy. Nonetheless, a bulk of patients have failed to respond to these newly emerging immune-based approach and the survival rate was not satisfying. Additional strategies, especially combination therapies, has been initiated and been further promising. Attempts to identify novel and well-suited predictive biomarkers are also sensed. In this review, the promotion of cancer immunotherapy targeting PD-1 immunoinhibitory pathway is discussed.

Duchenne muscular dystrophy: an updated review of common available therapies.

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy (DMD) is a lethal progressive pediatric muscle disorder and genetically inherited as an X-linked disease that caused by mutations in the dystrophin gene. DMD leads to progressive muscle weakness, degeneration, and wasting; finally, follows with the premature demise in affected individuals due to respiratory and/or cardiac failure typically by age of 30. For decades, scientists tried massively to find an effective therapy method, but there is no absolute cure currently for patients with DMD, nevertheless, recent advanced progressions on the treatment of DMD will be hopeful in the future. Several promising gene therapies are currently under investigation. These include gene replacement, exon skipping, suppression of stop codons. More recently, a promising gene editing tool referred to as CRISPR/Cas9 offers exciting perspectives for restoring dystrophin expression in patients with DMD. This review intents to briefly describe these methods and comment on their advances. Since DMD is a genetic disorder, it should be treated by replacing the deficient DMD copy with a functional one. However, there are different types of mutations in this gene, so such therapeutic approaches are highly mutation specific and thus are personalized. Therefore, DMD has arisen as a model of genetic disorder for understanding and overcoming of the challenges of developing personalized genetic medicines, consequently, the lessons learned from these approaches will be applicable to many other disorders. CONCLUSIONS: This review provides an update on the recent gene therapies for DMD that aim to compensate for dystrophin deficiency and the related clinical trials.