Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome.

Camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive disease caused by mutation in proteoglycan 4 (PRG4) gene on chromosome 1q25-q31. We faced a dilemma and delay in diagnosis in two sisters. The elder sister had pericardial effusion with constrictive pericarditis, underwent pericardiectomy and received empirical treatment for suspected tuberculosis. After 2 years, she developed bilateral knee swelling with restriction of movement. At the same time, her younger sister also presented with bilateral knee swelling which aroused the suspicion of genetic disease. The whole-genome sequencing revealed homozygous PRG4 mutation suggestive of CACP syndrome.

[Clinicopathological features and prognosis of sporadic mismatch repair deficient colorectal cancer].

Objective: To investigate the clinicopathological characteristics and prognostic factors of sporadic mismatch repair deficient (dMMR) colorectal cancer. Methods: A total of 120 cases of sporadic dMMR colorectal cancer from July 2015 to April 2021 were retrospectively collected in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Patients with Lynch syndrome; synchronous multiple colorectal cancers; preoperative anti-tumor treatments such as chemotherapy and radiotherapy; and those with incomplete follow-up information were excluded based on family history and next-generation sequencing (NGS) test results. Immunohistochemical stains were used to detect the expression of mismatch repair proteins, methylation-specific PCR for methylation testing, and fluorescent PCR for BRAF V600E gene mutation detection. The clinical and pathological data, and gene mutation status were analyzed. Follow-up was done to assess survival and prognosis including progression-free survival and overall survival rate. Results: Sporadic dMMR colorectal cancer occurred more frequently in the right side of the colon, in females, and in the elderly. Morphologically, it was mostly moderately-differentiated, and most patients had low-grade tumor budding. In terms of immunohistochemical expression, MLH1 and PMS2 loss were dominant, and there were age and location-specificities in protein expression. MLH1 methylation was commonly detected in elderly female patients and rare in young male patients; while MLH1 and PMS2 deficiency, and BRAF V600E mutation occurred more often on the right side (P<0.05). The 3-year and 5-year progression-free survival rates were 90.7% and 88.7% respectively, and the 3-year and 5-year overall survival rates were 92.8% and 90.7% respectively. Tumor budding status was an independent risk factor affecting patient recurrence (hazard ratio=3.375, 95% confidence interval: 1.060-10.741, P=0.039), patients with low-grade tumor budding had better prognosis, and those with medium or high-grade tumor budding had poor prognosis. Conclusion: For dMMR colorectal cancer patients, tumor budding status is an independent risk factor for recurrence.

[Clinicopathological and molecular genetic features of neuromuscular choristoma-associated desmoid type fibromatosis].

Objective: To investigate the clinicopathological and genetic characteristics of neuromuscular choristoma-associated desmoid type fibromatosis (NMC-DF). Methods: The clinical morphological and immunohistochemical features of 7 NMC-DF cases diagnosed from January 2013 to January 2023 in Beijing Jishuitan Hospital were retrospectively analyzed. A series of neuromuscular choristoma and neuromuscular choristoma-associated desmoid type fibromatosis were evaluated for CTNNB1 mutations, and hotspot mutations for CTNNB1 were tested in 4 NMC-DF cases using Sanger sequencing. Results: The tumors were collected from 3 females and 4 males, aged 1 to 22 years (mean 7.1 years), involving the sciatic nerve (n=4), brachial plexus (n=2) or multiple nerves (n=1). The course of the disease spanned from 3 months to 10 years. Two cases were recurrent tumors. All the 7 NMC cases showed endoneurial intercalation of mature skeletal muscle fibers among the peripheral nerve fascicles, and the histologic features of the NMC-DF were strikingly similar to the conventional desmoid-type fibromatosis. By immunohistochemistry, all NMC and NMC-DF cases showed aberrant nuclear staining of ß-catenin (7/7), the muscle cells in NMC were intensely immunoreactive for desmin, and the admixed nerve fibers were highlighted by NF and S-100 (7/7). Four NMC and NMC-DF had CTNNB1 mutations, 3 c.121A>G (p.T41A) and 1 c.134C>T (p.S45F). Follow-up of the 7 cases, ranging from 22 to 78 months, showed tumor recurrence in 2 patients at 3 and 8 months respectively after the first surgical resection, of which 1 patient underwent above-knee amputation. No recurrence occurred in other cases with tumor excision and neurological reconstruction surgery. There was no metastasis occurred in the 7 cases. Conclusions: NMC is a rare congenital lesion with differentiated mature skeletal muscle tissue found in peripheral nerve fascicles, and approximately 80% of patients with NMC develop a soft tissue fibromatosis. CTNNB1 mutation in the Wnt signaling pathway may be involved in the pathogenesis of NMC and NMC-DF, and S45F mutations seems to have a higher risk of disease progression.

Silencing of lncRNA LOC105376794 promotes migration, invasion, and Gefitinib resistance of lung adenocarcinoma cells with EGFR 19Del mutation by ATF4/CHOP axis and ERK phosphorylation.

Epidermal growth factor receptor (EGFR) gene exon 19 in-frame deletion (19del) and exon 21 L858R point mutation (21L858R mutation) are prevalent mutations in lung adenocarcinoma. Lung adenocarcinoma patients with 19del presented with a better prognosis than the 21L858R mutation under the same epidermal growth factor receptor tyrosine kinase inhibitor treatment. Our study aimed to uncover the expression of long non-coding RNA LOC105376794 between 19del and 21L858R mutation, and explore the mechanism that regulates cells' biological behavior and gefitinib sensitivity in lung adenocarcinoma cells with 19del. Transcriptome sequencing was conducted to identify differentially expressed lncRNAs between EGFR 19del and 21L858R mutation in serum through the DNBSEQ Platform. Protein-protein interaction network and Kyoto Encyclopedia of Genes and Genomes pathway were conducted to analyze the relationship between lncRNAs and mRNAs through STRING and Dr. TOM. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of lncRNA LOC105376794 in serum and cells. Loss-of-function experiments were used to validate the biological function and gefitinib sensitivity of LOC105376794 in lung adenocarcinoma cells. Protein levels were detected by western blotting. Through transcriptome resequencing and RT-qPCR, we found the expression levels of LOC105376794 in serum were increased in the 19del group compared with the 21L858R mutation group. Inhibition of LOC105376794 promoted proliferation, migration and invasion, and reduced apoptosis of HCC827 and PC-9 cells. The low expression of LOC105376794 reduced gefitinib sensitivity in PC-9 cells. Mechanistically, we found that the knockdown of LOC105376794 suppressed activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway and facilitated the expression of extracellular signal-regulated kinase 1/2 (ERK) phosphorylation. LOC105376794 altered cell biological behavior and gefitinib sensitivity of lung adenocarcinoma cells with 19del through the ATF4/CHOP signaling pathway and the expression of ERK phosphorylation. The results further illustrated the fact that lung adenocarcinoma patients with 19del presented with a more favorable clinical outcome and provided a theoretical basis for treatment strategy for lung adenocarcinoma patients with 19del.

[Clinical characteristics of myeloid tumors combined with the proliferation of large granular lymphocytes].

Myeloid neoplasms (MNs) belong to a group of hematological malignancies characterized by the abnormal biological functions of hematopoietic stem progenitor cells. The abnormal immune and hematopoietic microenvironment of patients with MN interact with malignant clonal hematopoietic stem cells, promoting the occurrence and development of their diseases. MN large granular lymphocyte proliferation (MN-LGLP) is a special and rare clinical phenomenon in this type of disease. Currently, research on this disease in domestic and international cohorts is limited. This study analyzes the clinical and laboratory characteristics of this type of patient and explores the impact of LGLP on the clinical characteristics and survival of patients with MN. Patients with MN-LGLP are prone to neutropenia and splenomegaly. The presence of LGLP is not a risk factor affecting the survival of patients with MN-LGLP. STAG, ASXL1, and TET2 are the most common accompanying gene mutations in MN-LGLP, and patients with MN-LGLP and STAG2 mutations have poor prognoses.

[Analysis of risk factors for venous thromboembolism in patients with polycythemia vera and establishment of a prediction model].

Objective: To investigate the risk factors of venous thrombosis in patients with polycythemia vera (PV) and establish a prediction model for venous thrombosis. Methods: PV patients with JAK2V617F gene mutation positive in the Second Hospital of Tianjin Medical University from September 2017 to November 2023 were retrospectively included. The patients were divided into groups according to whether they had venous thrombosis. After matching age and gender factors with propensity scores, 102 patients were included in the venous thrombosis group [46 males, 56 females, with a median age M (Q1, Q3) of 52 (44, 60) years] and 204 cases were included in the group without venous thrombosis [92 males, 112 females, with a median age of 52 (44, 59) years]. The clinical and laboratory characteristics, disease progression and incidence of gene mutation were compared between the two groups. The follow-up cohort ended on November 20, 2023, with a median follow-up [M (Q1, Q3)] of 11 (1, 53) years. Multivariate Cox risk model was used to analyze the influencing factors of venous thrombosis in PV patients, and establish a scoring system for the venous thrombosis risk factor prediction model of PV patients. Receiver operating characteristic (ROC) curve was used to evaluate the predictive efficiency of the model. Results: Hemoglobin concentration, the ratio of hematopoietic volume≥55%, neutrophil to lymphocyte ratio≥5, hypertension, subcostal spleen≥5 cm and secondary myelofibrosis in venous thrombosis group were higher than those in non-venous thrombosis group (all P<0.05). In addition, the proportion of history of thromboembolism, V617F gene mutation load (V617F%)≥50%, diabetes mellitus, ASXL1 mutation and secondary reticular silver staining≥3 in the venous thrombosis group were higher than those in the non-venous thrombosis group (all P<0.05). The proportion of PV patients with 3 or more gene mutations was 44.1% (45/102) in venous thrombosis group, which was higher than that of PV patients without venous thrombosis 29.9% (61/204) (P=0.014). The proportion of ASXL1 gene mutation in venous thrombosis group was 17.6% (18/102), which was higher than the 4.9% (10/204) in non-venous thrombosis group (P<0.001). Multivariate Cox risk model analysis showed that previous thromboembolism history (HR=2.031, 95%CI: 1.297-3.179, P=0.002), V617F%≥50% (HR=2.141, 95%CI: 1.370-3.347, P=0.001), ASXL1 mutation (HR=4.632, 95%CI: 1.497-14.336, P=0.008), spleen subcostal≥5 cm (HR=1.771, 95%CI: 1.047-2.996, P=0.033) are the risk factors of venous thrombosis in PV patients. According to HR values, a score system for predicting risk of venous thrombosis in PV patients was established: previous history of thromboembolism, V617F%≥50% and spleen subcostoal≥5 cm were assigned 1 point respectively, and ASXL1 mutation was assigned 2 points. Low risk group: score 0, medium risk group: score 1-2, high risk group: score≥3. The ROC curve analysis of the model for predicting venous thrombosis in PV patients showed that the area under the curve (AUC) was 0.807 (95%CI: 0.755-0.860), with the sensitivity of 88.2% and the specificity of 59.8% when the Youden index was 0.48. Conclusions: Previous thromboembolism history, V617F%≥50%, ASXL1 mutation, spleen subcostoal≥5 cm are risk factors of venous thrombosis in PV patients. The established prediction model has good prediction efficiency.

Clonal Hematopoiesis-Associated Gene Mutations Affect Acute Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation in AML Patients.

BACKGROUND The relationship between clonal hematopoiesis (CH)-associated gene mutations and allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been extensively studied since next-generation sequencing (NGS) technology became widely available. However, research has mainly focused on the relationship between donor CH mutations and transplant prognosis, and research into the relationship between CH mutations in the recipient and acute graft-versus-host disease (aGVHD) is lacking. MATERIAL AND METHODS We analyzed NGS results and their correlation with aGVHD and prognosis in 196 AML patients undergoing allo-HSCT. RESULTS A total of 93 (47.4%) patients had CH mutations. The most frequently mutated genes were DNMT3A (28 of 196; 14.3%), TET2 (22 of 196; 11.2%), IDH1 (15 of 196; 7.7%), IDH2 (14 of 196; 7.1%), and ASXL1 (13 of 196; 6.6%). The incidence of aGVHD was higher in patients older than 45 years old with DTA mutations (DNMT3A, TET2 or ASXL1). DNMT3A mutation but not with TET2 or ASXL1 mutation was an independent risk factor for aGVHD in patients receiving allo-HSCT older than 45 years old. With a median follow-up of 42.7 months, CH mutations were not associated with overall survival and leukemia-free survival. CONCLUSIONS DNMT3A mutation, but not TET2 or ASXL1 mutation, was associated with higher incidence of aGVHD.

[Genetic analysis of a Chinese pedigree affected with Cowden syndrome due to variant of PTEN gene].

OBJECTIVE: To explore the clinical features and genetic etiology of a Chinese pedigree affected with Cowden syndrome (CS). METHODS: A CS pedigree diagnosed in November 2022 at the Ningde Municipal Hospital Affiliated to Ningde Normal University was selected as the study subject. Clinical data were collected, and genetic testing was carried out for available members. Pathogenicity analysis was carried out for the candidate variant. RESULTS: The proband, a 7-year-old male, was found to have autism and intellectual disability. Whole exome sequencing revealed that he has harbored a c.462_463del (p.F154Lfs25) variant of the PTEN gene. The proband's 35-year-old mother, who was diagnosed with pulmonary hamartomas at our hospital, has manifested with lipomas, nodular goiter, and adenomas. Sanger sequencing confirmed that she was also heterozygous for the c.462_463del (p.F154Lfs25) variant of the PTEN gene. No other family members has carried the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+PM2_Supporting+PM6). CONCLUSION: The newly discovered c.462_463del (p.F154Lfs*25) variant of the PTEN gene probably underlay the CS in this pedigree. CS patients have higher risk for developing malignant tumors. Clinicians should be aware of this condition and emphasize follow-up of the patients.

Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade.

The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

A Visual Analysis of the Research Dynamics in Resistance to EGFR Inhibitors for NSCLC.

Purpose: Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), aiding in improving patient response rates and survival. However, resistance challenges the efficacy of these treatments, with limited understanding of post-resistance therapeutic strategies. A deep understanding of the biology and resistance mechanisms of EGFR-mutant NSCLC is crucial for developing new treatment approaches. This study, through bibliometric analysis, summarizes the trends in research on resistance to EGFR-TKIs. Methods: Research papers on NSCLC with EGFR inhibitor resistance were collected from the Web of Science Core Collection (WoSCC). The analysis utilized bibliometric tools like CiteSpace, VOSviewer, and other platforms for comprehensive analysis and visualization of the outcomes. Results: The WoSCC database contains a total of 5866 documents on resistance to EGFR-TKIs treatment, including 4727 articles (93.48%) and 1139 reviews (6.52%), spanning 81 countries and regions, 4792 institutions, with the involvement of 23,594 authors. Since 2016, there has been a significant increase in publications in this field. China has the highest publication output, while the United States has the highest citation count for papers. Harvard University leads in terms of the number of publications. Among the top ten journals with the highest output, Clinical Cancer Research has the highest impact factor at 11.5, with 90% of the journals classified in Q1 or Q2. Rafael Rosell is one of the most influential authors in this field, ranking second in publication volume and fourth in citation count. Research on EGFR-TKIs resistance mainly focuses on genetic testing, resistance mechanisms, and post-resistance treatment strategies. Conclusion: This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and exploring potential directions.

Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.

Revisiting the evolution of bow-tie architecture in signaling networks.

Bow-tie architecture is a layered network structure that has a narrow middle layer with multiple inputs and outputs. Such structures are widely seen in the molecular networks in cells, suggesting that a universal evolutionary mechanism underlies the emergence of bow-tie architecture. The previous theoretical studies have implemented evolutionary simulations of the feedforward network to satisfy a given input-output goal and proposed that the bow-tie architecture emerges when the ideal input-output relation is given as a rank-deficient matrix with mutations in network link intensities in a multiplicative manner. Here, we report that the bow-tie network inevitably appears when the link intensities representing molecular interactions are small at the initial condition of the evolutionary simulation, regardless of the rank of the goal matrix. Our dynamical system analysis clarifies the mechanisms underlying the emergence of the bow-tie structure. Further, we demonstrate that the increase in the input-output matrix reduces the width of the middle layer, resulting in the emergence of bow-tie architecture, even when evolution starts from large link intensities. Our data suggest that bow-tie architecture emerges as a side effect of evolution rather than as a result of evolutionary adaptation.

[Cancer genomic panels for lymphoid malignancies].

Cancer precision medicine (genome-based individualized treatment for cancer patients) has already been introduced for solid tumors, and involves identifying driver genes in the development and progression of tumors and suggesting optimal treatments targeting those genes. So far, many patients have received this style of treatment. Meanwhile, preparations for cancer genomic medicine based on cancer gene panel testing are also underway for hematopoietic tumors. In this article, I would like to share fundamental information about the main genetic mutations in malignant lymphomas and their clinical significance, and discuss how this information should be utilized in cancer genomic medicine in the future.

Valosin-Containing Protein (VCP)/p97 Oligomerization.

Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.

Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.

Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.