Identification of tissue biomarkers of prognostic significance in pancreatic cancer

Background: Pancreatic cancer is the third leading cause of cancer-related mortality. Lack of early detection strategies and therapeutic resistance are main contributors to the poor prognosis. Unfortunately, there are no tissue biomarkers available for the prognosis of pancreatic cancer in routine clinical use.Aim: To identify and validate novel tissue biomarkers for the prognosis of pancreatic cancer.Methods: A mass spectrometry-based proteomic approach was applied to formalin-fixed paraffin-embedded specimens from surgically resected pancreatic cancer in 9 patients with short survival (45 months). The dysregulated biomarkers were further verified by targeted proteomics, parallel reaction monitoring. Finally, we evaluated prognostic candidates (CLCA1, galectin 4, P4HA2, PRTN3 and fibronectin) by tissue microarray and immunohistochemistry in a larger cohort of patients with pancreatic cancer who underwent surgical resection (n=144). Bioinformatic analysis was exploited to assess pathways and networks linked to the prognosis. Kaplan-Meier and Cox proportional hazards modeling were used to explore the association between biomarkers and survival.Results/Conclusion: A total of 24 and 147 proteins were significantly upregulated in patients with short survival and long survival, respectively. Bioinformatic analysis linked proteins representing “activated stroma factors” and “basal tumor factors” to poor prognosis and highlighted TCF1 and CTNNB1 as possible upstream regulators. By targeted proteomics, seven proteins were verified to be upregulated in patients with short survival (MMP9, CLIC3, MMP8, PRTN3, P4HA2, THBS1 and FN1), while 18 proteins were upregulated in patients with long survival, including EPCAM, galectin 4, VIL1, CLCA1 and TPPP3 (I). By immunohistochemical validation, we found that low CLCA1 expression correlated significantly with shorter disease-free survival (II). Furthermore, galectin 4 expression significantly correlated with disease recurrence within 1 year of surgery and with overall survival at 1- and 3-year (III). Besides, a low P4HA2 and high PRTN3 expression pattern correlated with shorter disease-free survival and overall survival (IV). Finally, high stromal FN1 expression was associated with aggressive tumor characteristics in patients with resected pancreatic cancer, although it was not associated with survival (V)

Noninvasive prenatal diagnosis of 21-Hydroxylase deficiency using target capture sequencing of maternal plasma DNA.

Here, we aimed to validate a noninvasive method using capture sequencing for prenatal diagnosis of congenital adrenal hyperplasia due to 21-Hydroxylase deficiency (21-OHD). Noninvasive prenatal diagnosis (NIPD) of 21-OHD was based on 14 plasma samples collected from 12 families, including four plasma sample collected during the first trimester. Targeted capture sequencing was performed using genomic DNA from the parents and child trios to determine the pathogenic and wild-type alleles associated with the haplotypes. Maternal plasma DNA was also sequenced to determine the fetal inheritance of the allele using hidden Markov model-based haplotype linkage analysis. The effect of fetal DNA fraction and sequencing depth on the accuracy of NIPD was investigated. The lower limit of fetal DNA fraction was 2% and the threshold mean sequence depth was 38, suggesting potential advantage if used in early gestation. The CYP21A2 genotype of the fetus was accurately determined in all the 14 plasma samples as early as day 1 and 8 weeks of gestation. Results suggest the accuracy and feasibility of NIPD of 21-OHD using a small target capture region with a low threshold for fetal DNA fraction and sequence depth. Our method is cost-effective and suggests diagnostic applications in clinical practice

Effectiveness and safety of anti-BCMA chimeric antigen receptor T-cell treatment in relapsed/refractory multiple myeloma: a comprehensive review and meta-analysis of prospective clinical trials

Background: Chimeric antigen receptor T cells treatment targeting B cell maturation antigen (BCMA) is an emerging treatment option for relapsed/refractory multiple myeloma (RRMM) and has demonstrated outstanding outcomes in clinical studies.Objective: The aim of this comprehensive review and meta-analysis was to summarize the effectiveness and safety of anti-BCMA CAR-T treatment for patients with relapsed/refractory multiple myeloma (RRMM). Our research identifies variables influencing outcome measures to provide additional evidence for CAR-T product updates, clinical trial design, and clinical treatment guidance.Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard was followed for conducting this comprehensive review and meta-analysis, which was submitted to PROSPERO (CRD42023390037). From the inception of the study until 10 September 2022, PubMed, Web of Science, EMBASE, the Cochrane Library, CNKI, and WanFang databases were searched for eligible studies. Stata software (version 16.0) was used to assess effectiveness and safety outcomes.Results: Out of 875 papers, we found 21 relevant trials with 761 patients diagnosed as RRMM and were given anti-BCMA CAR-T treatment. The overall response rate (ORR) for the entire sample was 87% (95% CI: 80–93%) complete response rate (CRR) was 44% (95% CI: 34–54%). The minimal residual disease (MRD) negativity rate within responders was 78% (95% CI: 65–89%). The combined incidence of cytokine release syndrome was 82% (95% CI: 72–91%) and neurotoxicity was 10% (95% CI: 5%–17%). The median progression-free survival (PFS) was 8.77 months (95% CI: 7.48–10.06), the median overall survival (OS) was 18.87 months (95% CI: 17.20–20.54) and the median duration of response (DOR) was 10.32 months (95% CI: 9.34–11.31).Conclusion: According to this meta-analysis, RRMM patients who received anti-BCMA CAR-T treatment have demonstrated both effectiveness and safety. Subgroup analysis confirmed the anticipated inter-study heterogeneity and pinpointed potential factors contributing to safety and efficacy, which may help with the development of CAR-T cell studies and lead to optimized BCMA CAR-T-cell products.Systematic Review Registration:Clinicaltrials.gov, PROSPERO, CRD42023390037

Identifying Novel Copy Number Variants in Azoospermia Factor Regions and Evaluating Their Effects on Spermatogenic Impairment

Microdeletions in Y-chromosomal azoospermia factor (AZF) regions have been regarded as the risk factor of spermatogenic failure (SF). However, AZF-linked duplications or complex copy number variants (CNVs) (deletion + duplication) were rarely studied. In this study, we performed multiplex ligation-dependent probe amplification (MLPA) analysis on 402 fertile healthy male controls and 423 idiopathic infertile SF patients (197 azoospermia and 226 oligozoospermia) in Han Chinese population. In total, twenty-four types of AZF-linked CNVs were identified in our study, including eleven novel CNVs (one deletion, seven duplications, and three complex CNVs). Our study revealed that AZFc-linked duplications and the instability of Y chromosome might be associated with spermatogenesis. Besides, the complex CNVs (b2/b3 deletion + DAZ1/2 duplication) were confirmed to increase genetic risks for SF in Han Chinese population. This study illustrated a spectrum of AZF-linked CNVs and presented valuable information for understanding the clinical significance of AZF-linked CNVs in male infertility

Prenatal Diagnosis of Recurrent Distal 1q21.1 Duplication in Three Fetuses With Ultrasound Anomalies

Background: The phenotype of duplication of 1q21.1 region is variable, ranging from macrocephaly, autism spectrum disorder, congenital anomalies, to a normal phenotype. Few cases have been reported in the literature regarding prenatal diagnosis of 1q21.1 duplication syndrome. The current study presents prenatal diagnosis of 1q21.1 duplication syndrome in three fetuses with ultrasound anomalies.Case presentation: Three fetuses from three unrelated families were included in the study. The prenatal routine ultrasound examination showed nasal bone loss in Fetus 1 and Fetus 3, as well as duodenal atresia in Fetus 2. Chromosomal microarray analysis was performed to provide genetic analysis of amniotic fluid and parental blood samples. The CMA results revealed two de novo duplications of 1.34 and 2.69 Mb at distal 1q21.1 region in two fetuses with absent nasal bone, as well as a maternal inherited 1.35-Mb duplication at distal 1q21.1 in one fetus with duodenal atresia.Conclusions: The phenotype of 1q21.1 duplication syndrome in prenatal diagnosis is variable. The fetuses with nasal bone loss or duodenal atresia may be related to 1q21.1 duplication and chromosomal microarray analysis should be performed

Proteomic and genomic profiling of pancreatic cancer

Pancreatic cancer remains the most fatal human tumor type. The aggressive tumor biology coupled with the lack of early detection strategies and effective treatment are major reasons for the poor survival rate. Collaborative research efforts have been devoted to understand pancreatic cancer at the molecular level. Large-scale genomic studies have generated important insights into the genetic drivers of pancreatic cancer. In the post-genomic era, protein sequencing of tumor tissue, cell lines, pancreatic juice, and blood from patients with pancreatic cancer has provided a fundament for the development of new diagnostic and prognostic biomarkers. The integration of mass spectrometry and genomic sequencing strategies may help characterize protein identities and post-translational modifications that relate to a specific mutation. Consequently, proteomic and genomic techniques have become a compulsory requirement in modern medicine and health care. These types of proteogenomic studies may usher in a new era of precision diagnostics and treatment in patients with pancreatic cancer

Evolution from Periodic Intensity Modulations to Dissipative Vector Solitons in A Single-Mode Fiber Laser

We investigated—both experimentally and numerically—the operation of a weakly birefringent cavity fiber laser under different net cavity dispersion values. Experimentally, we found that under coherent cross-polarization coupling, either in-phase or anti-phase low frequency intensity modulations between the two orthogonal polarization components of the laser emission could be obtained. The evolution of the periodic intensity modulations in the fiber laser under different operation conditions was studied. In this paper, we show that under suitable conditions, they can be shaped into a train of bright-bright, dark-dark, or dark-bright vector solitons