Loss-of-function mutation of REV1 (p.R704Q) mediates cetuximab primary resistance by activating autophagy in RAS-wild type metastatic colorectal cancer.

Cetuximab in combination with FOLFIRI/FOLFOX is the standard first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). However, some patients experience rapid tumor progression after treatment with cetuximab (primary resistance). Our previous research identified a gene mutation, REV1 p.R704Q, which may be a key biomarker for primary cetuximab resistance. This study aimed to study the mechanism of cetuximab resistance caused by REV1 p.R704Q mutation and reveal a novel mechanism to induce cetuximab resistance. Sanger sequencing and multivariate clinical prognostic analysis of 208 patients with mCRC showed that REV1 p.R704Q mutation is an independent risk factor for tumor progression after treatment with cetuximab in patients with RAS wild-type mCRC (Hazard ratio=2.481, 95% Confidence interval: 1.389-4.431, P = 0.002). The sensitivity of REV1 p.R704Q mutant cell lines to cetuximab decreased in vitro Cell Counting Kit-8 assay and in vivo subcutaneous tumor model. In vitro, we observed that decreased stability and accelerated degradation of REV1 mutant protein results in REV1 dysfunction, which activated autophagy and mediated cetuximab resistance. These findings suggested that REV1 p.R704Q mutation could predict cetuximab primary resistance in mCRC. REV1 p.R704Q mutation caused decreased stability and degradation of REV1 protein, as well as dysfunction of p.R704Q protein. REV1 p.R704Q mutation activates autophagy and mediates cetuximab resistance; further, inhibition of autophagy could reverse cetuximab resistance.

Deep-sea caridean shrimps collected from the South China Sea with emphasizing their phylogenetic relationships.

Despite the high biological and ecological diversity of the South China Sea, limited research has been conducted on the deep-sea species diversity of caridean shrimps. Based on the collections from three scientific expeditions conducted in the South China Sea, 31 caridean species, belonging to nine families, were reported, including the identification of two species not previously documented in this region, namely Janicella spinicauda (A. Milne-Edwards, 1883) and Systellaspis curvispina Crosnier, 1988. In addition to morphological features, the COI and 16S gene sequences of these species were analyzed to assess their evolutionary relationships within each family. Phylogenetic analyses, with highest species coverage to date, indicated that similarity in morphological characteristics does not always lead to closer phylogenetic relationships and some defining characteristics for specific taxa are not always synapomorphies but may be the result of convergent evolution. Our results establish reliable evolutionary relationships within specific taxa and highlight the necessity for further taxonomic revisions within these taxa.

Camrelizumab, chemotherapy and apatinib in the neoadjuvant treatment of resectable oesophageal squamous cell carcinoma: a single-arm phase 2 trial.

Background: In resectable oesophageal squamous cell carcinoma (ESCC), the efficacy of camrelizumab combined with chemotherapy and apatinib followed by minimally invasive oesophagectomy is not clear. We aimed to fill this knowledge gap. Methods: This investigator-initiated, single-arm, prospective, phase 2 trial was performed at the Second Affiliated Hospital of Zhejiang University, China. Patients (aged 18-75 years) who were histologically or cytologically diagnosed with ESCC were deemed suitable to participate in this trial. Patients received 2-3 cycles of neoadjuvant therapy with camrelizumab, nedaplatin, albumin paclitaxel, and apatinib; each cycle was repeated every 14 days. Surgery occurred 4-6 weeks after the last neoadjuvant treatment cycle. The primary outcome was the pathological complete response (PCR) rate of the tumour and lymph nodes. The changes in the peripheral blood immunoprofile among patients without PCR (ie, non-PCR [NPCR]) and with PCR were assessed by mass cytometry. This study was registered with ClinicalTrials.gov, NCT04666090. Findings: 42 patients were enrolled between November 23, 2020 and December 31, 2022. The disease control rate was 100.0% (95% CI, 91.6-100%), and the objective response rate was 83.3% (95% CI, 68.6-93.0%). Six (14.3%) patients experienced grade 3 adverse events. The most common were white blood cell count decrease (31.0%), alopecia (81.0%), asthenia (38.1%), and reactive cutaneous capillary endothelial proliferation (35.7%). 41 patients received minimally invasive oesophagectomy; all 41patients achieved R0 resection, and 18 (43.9%, 95% CI, 28.5-60.3%) patients achieved PCR. The median follow-up was 23 months and the 2-year survival rate was 85.9%. T-cell subsets in both the PCR and NPCR groups exhibited consistency in response to neoadjuvant therapy. In contrast, some of natural killer (NK) cells (NK-C03, NK-C11), B cells (B-C06) and monocytes (M-C05), exhibited significant differences between the PCR and NPCR groups before neoadjuvant therapy. M-C06 had a significant difference in the PCR group and NPCR group after neoadjuvant therapy. NK-C12 and B-C15 showed significant differences both before and after neoadjuvant therapy. Interpretation: The application of camrelizumab, chemotherapy and apatinib in the neoadjuvant setting for locally advanced ESCC has shown promising antitumour activity and an acceptable safety profile in this single-arm study. In the neoadjuvant setting, NK cell, B cell, and monocyte subsets exhibited greater predictive power for immunotherapy responsiveness than T-cell subsets. Longer follow-up to assess survival outcomes and a phase 3 randomised trial are needed to further evaluate the proposed treatment. Funding: The China Anti-Cancer Association and the "Leading Goose" Research and Development Project of Zhejiang Province.

Phylogenetics and Population Genetics of the Petrolisthes lamarckii-P. haswelli Complex in China: Old Lineage and New Species.

Petrolisthes lamarckii (Leach, 1821) and P. haswelli Miers, 1884 are a pair of sister species of porcelain crabs, both of which are common in the intertidal zone of southern China, typically found under rocks and in the crevices of coral reefs. However, the distribution, genetic relationship and diversity of the two species in China have not been rigorously studied. Meanwhile, P. lamarckii is considered as a complex of cryptic species due to their diverse morphological features. In this study, we identified 127 specimens of the P. lamarckii-P. haswelli complex (LH complex) and recognised a new species through morphological and molecular analysis. Furthermore, we constructed a time-calibrated phylogeny of the LH complex using three mitochondrial and two nuclear genes from all three species, finding that the divergence of the LH complex can be traced back to the Miocene epoch, and that the genetic diversity increased during the Mid-Pleistocene transition period. Glacial refugia formed during the Pleistocene climatic oscillations has been regarded as one of the contributing factors to the diversification of marine organisms in the north-western Pacific. Petrolisthes haswelli demonstrates a wide distribution along the southern coast of China, while other lineages display more restricted distributions. The research on the demographic history and gene flow of P. haswelli revealed that the Chinese coastal populations experienced an expansion event approximately 12.5 thousand years ago (Kya) and the asymmetrical gene flows were observed between the two sides of the Taiwan Strait and Qiongzhou Strait, respectively, which is likely influenced by the restriction of ocean currents.

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial.

Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC. Methods: This study was an open-label, single-arm, phase II trial in China. Patients with unresectable, RAS-mutant and MSS metastatic colorectal adenocarcinoma received treatment by intravenous sintilimab (200 mg, day 1) plus bevacizumab (7.5 mg/kg, day 1), oxaliplatin (135 mg/m2, day 1) and oral capecitabine (1 g/m2, day 1-14) in each 21-day cycle. The primary endpoints included objective response rate (ORR) and adverse events. Biomarker analysis was performed to identify potential predictors of good response to treatment. This study is registered with ClinicalTrials.gov, number NCT04194359. Findings: Between April 2021 and December 2021, 25 patients were enrolled. Two (8%) patients showed complete response (CR), 19 (76%) had partial response (PR) and 4 (16%) presented with stable disease. ORR reached 84% (95% CI, 63.9-95.5) and the disease control rate was 100% (95% CI, 86.3-100). The median progression-free survival (PFS) was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84%), neutropenia (20/25, 80%), and hand-foot syndrome (14/25, 56%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12%) and increased alanine transaminase (2/25, 8%). No grade 5 adverse events occurred. In the exploration of biomarkers, 5 patients could be characterized as TTN/OBSCN "double-hit" after treatment, and the copy number variants burden was significantly decreased in tumor tissues after treatment compared with the baseline. Nanostring panel RNA sequencing analysis indicated a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients as well as the PFS-long (≥12.5 months) group compared with the PFS-short group. Interpretation: Combination treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line treatment demonstrated a promising antitumor activity and a manageable safety profile in RAS-mutant, MSS and unresectable mCRC. Exploratory biomarker assessment analysis showed that some RAS-mutant and MSS patients changed into "immune-hot" subtype after the treatment. Funding: This study was supported by the Key R&D Program of Zhejiang Province (2021C03125 to Ying Yuan), the National Natural Science Foundation of China (81872481 to Ying Yuan, 82072624 to Kefeng Ding), the Fundamental Research Funds for the Central Universities (No. 226-2022-00009 to Kefeng Ding), and the Zhejiang Provincial Natural Science Foundation of China (No. LY22H160024 to Hanguang Hu).

The Genomic and Proteomic Profiles of NTRK Genes and Trk Receptors in Liver Hepatocellular Carcinoma.

Background: The neurotrophic tyrosine kinase (NTRK) gene family includes NTRK1, NTRK2, and NTRK3, which encode tropomyosin receptor kinases TrkA, TrkB, and TrkC, respectively. This study aimed to initially assess the genomic and proteomic profiles of NTRK genes and Trk receptors in liver hepatocellular carcinoma (LIHC). Methods: The ONCOMINE, UALCAN, GEPIA, cBioPortal, FusionGDB, SurvivalMeth, and the Human Protein Atlas databases were searched for NTRK gene expression and protein data in LIHC. Immunohistochemistry was used to detect pan-Trk expression across a commercial microarray containing 96 hepatocellular carcinoma (HCC) and 94 para-cancerous tissue spots. A modified histological score (H-score) with a maximum score of 300 was used to quantify immunohistochemical staining for pan-Trk. Student's t- and chi-square tests were the main statistical analyses used. Results: The transcriptional levels of NTRK genes in LIHC were not significantly different from healthy controls. Using UALCAN and GEPIA, only high expression of NTRK2 was significantly associated with longer disease-free survival (P = 0.004). The alteration frequencies were low (7% in NTRK1, 1.7% in NTRK2, and 2% in NTRK3). The methylation levels of NTRK genes were all significantly different as analyzed by UALCAN; the high-risk group displayed an unfavorable prognosis compared with the low-risk group for NTRK1 (P = 0.033) and NTRK3 (P = 0.005). The median H-score of pan-Trk in HCC and para-cancerous tissues was not statistically different (186.31 ± 23.86 and 192.38 ± 21.06, P = 0.065). No differences were observed in clinicopathological features of HCC with the median H-score for pan-Trk expression (p > 0.05). The survival rate of patients with pan-Trk expression was also not significantly different. Conclusion: The alteration frequency was low in NTRK genes, including gene fusion and methylation levels. Therefore, pan-Trk expression in HCC tissue has limited value in clinicopathological features and prognosis.

Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study.

BACKGROUND: Rat sarcoma viral oncogene homolog (RAS) gene mutation is a common molecular event in colorectal cancer (CRC). The prognosis of mCRC (metastatic colorectal cancer) patients with RAS mutation is poor and capecitabine and oxaliplatin (CapeOx) plus bevacizumab has shown to be one of the standard therapeutic regimens as first line for these patients with objective response rate (ORR) of ~ 50% and median progression-free survival (mPFS) of 8-9 months. Immunotherapy, especially anti-programmed death 1 (PD-1) monoclonal antibody has demonstrated ground-breaking results in deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) mCRC patients. However, the response rate of in microsatellite stable (MSS) patients is extremely low. In addition, preclinical studies have demonstrated that anti-Vascular endothelial growth factor (VEGF) agents, such as bevacizumab, can induce tumor vascular normalization and enhance antitumor immunity. Previous study indicated the combination of chemotherapy, anti-VEGF agents (bevacizumab) with immune checkpoint inhibitors may have promising clinical activity in RAS mutant, MSS refractory mCRC patients. Based on these evidences, we will explore the combination of CapeOx with bevacizumab and sintilimab (anti-PD-1 monoclonal antibody) in RAS mutant, MSS mCRC patients as first-line therapy. METHODS: This is a randomized, open-label, multicentric clinical trial. In the sintilimab arm, patients will receive sintilimab in combination with CapeOx and bevacizumab. In the control arm, patients will receive CapeOx and bevacizumab. This trial will recruit 494 patients from 20 centers and randomly (1:1) disseminated into two groups. The primary endpoint is the PFS. The secondary endpoints include overall survival, safety, ORR, and disease control rate. DISCUSSION: This study may provide new ideas for optimizing oncology treatment planning for RAS mutant, MSS mCRC patients in the first-line set. TRIAL REGISTRATION: This study is short for BBCAPX and has been registered at clinicaltrials.gov registry with identifier NCT05171660.

Expression and prognostic impact of NTF3 and TrkC in hepatocellular carcinoma.

BACKGROUND: Treatment of patients with NTRK fusion-positive cancers using first-generation tropomyosin-related kinase (Trk) inhibitors is associated with high response rates, regardless of tumor histology. However, there have been few studies on neurotrophin-3 (NTF3) and TrkC ligands in hepatocellular carcinoma (HCC). METHODS: We used immunohistochemistry to evaluate NTF3 and TrkC expression levels in tissue samples. Gene expression profiling interactive analysis was used to determine TrkC and NTF3 expression in HCC. Western blotting, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assays were utilized to analyze TrkC and NTF3 levels in HCC cell lines. Proliferation tests and cell migration were also explored. RESULTS: NTF3 and TrkC levels were lower in HCC tissue (median H- scores 149.09 and 54.60, respectively) than those in para-cancerous tissue (192.69 and 71.70, respectively); no statistical difference was found in the survival rate. Positive correlations were observed between NTF3 and TrkC levels in both HCC and para-cancerous tissues. Alpha-fetoprotein was the only clinical characteristic associated with TrkC levels. The transcription of NTF3 was lower in HCC samples compared to normal samples. NTF3 overexpression inhibited the proliferation of MHCC97-L and HepG2 cells but did not significantly affect cell migration. CONCLUSIONS: The transcription of NTF3 was lower in HCC samples compared to normal samples, indicating a potential association with disease-free survival and overall survival in HCC. NTF3 and TrkC expression levels were lower in HCC tissues than those in para-cancerous tissues. Our results indicate that NTF3 may be a prognostic factor for HCC.

REV1: A novel biomarker and potential therapeutic target for various cancers.

Background: REV1 is a member of the translesion synthesis DNA polymerase Y family. It is an essential player in a variety of DNA replication activities, and perform major roles in the production of both spontaneous and DNA damage-induced mutations. This study aimed to explore the role of REV1 as a prognostic biomarker and its potential function regulating the sensitivity of anti-tumor drugs in various cancers. Methods: We analyzed the impact of REV1 gene alterations on patient prognosis and the impact of different REV1 single nucleotide polymorphisms (SNP) on protein structure and function using multiple online prediction servers. REV1 expression was assessed using data from Oncomine, TCGA, and TIMER database. The correlation between REV1 expression and patient prognosis was performed using the PrognoScan and Kaplan-Meier plotter databases. The IC50 values of anti-cancer drugs were downloaded from the Genomics of Drug Sensitivity in Cancer database and the correlation analyses between REV1 expression and each drug pathway's IC50 value in different tumor types were conducted. Results: Progression free survival was longer in REV1 gene altered group comparing to unaltered group [Median progression free survival (PFS), 107.80 vs. 60.89 months, p value = 7.062e-3]. REV1 SNP rs183737771 (F427L) was predicted to be deleterious SNP. REV1 expression differs in different tumour types. Low REV1 expression is associated with better prognosis in colorectal disease specific survival (DSS), disease-free survival (DFS), gastric overall survival (OS), post progression survival (PPS) and ovarian (OS, PPS) cancer while high REV1 expression is associated with better prognosis in lung [OS, relapse free survival (RFS), first progession (FP), PPS] and breast (DSS, RFS) cancer. In colon adenocarcinoma and rectum adenocarcinoma and lung adenocarcinoma, low expression of REV1 may suggest resistance to drugs in certain pathways. Conversely, high expression of REV1 in acute myeloid leukemia, brain lower grade glioma, small cell lung cancer and thyroid carcinoma may indicate resistance to drugs in certain pathways. Conclusion: REV1 plays different roles in different tumor types, drug susceptibility, and related biological events. REV1 expression is significantly correlated with different prognosis in colorectal, ovarian, lung, breast, and gastric cancer. REV1 expression can be used as predictive marker for various drugs of various pathways in different tumors.

Identification and prognostic analysis of the cetuximab resistance-related gene REV1 in RAS wild-type metastatic colorectal cancer.

The survival of patients with RAS wild-type metastatic colorectal cancer (mCRC) has improved markedly since the introduction of cetuximab, which is an anti-epidermal growth factor receptor monoclonal antibody. However, not all RAS wild-type patients respond to cetuximab treatment. Although some genetic alterations associated with cetuximab resistance have been identified, they cannot fully explain all cases of cetuximab resistance. Thus, in this research, we aimed to identify new genetic alterations associated with resistance to this treatment. The study retrospectively analyzed 70 patients diagnosed with RAS wild-type mCRC at our hospital between November 2009 and July 2018. First, five progression-free survival (PFS)-longest and 5 PFS-shortest tumor deoxyribonucleic acid were analyzed by whole-exome sequencing (WES) to identify differentially mutated genes. Then, PFS analysis of the 70 patients was used to verify the correlation between the candidate gene and cetuximab sensitivity. Finally, data from public databases were used to further verify the relationship between the mRNA expression level of the candidate gene and cetuximab responsiveness. The WES results indicated REV1: c.2108G > A was a candidate gene mutation related to the effectiveness of cetuximab. Survival analysis suggested REV1: c.2108G > A was associated with rapid disease progression (median PFS time, REV1 mutant vs. REV1 wild-type: 4.4 months vs. 8.7 months, P = 0.034). Data from the Genomics of Drug Sensitivity in Cancer and the Gene Expression Omnibus databases suggested low REV1 mRNA levels might be related to the poor response of CRC cells and reduced cetuximab efficacy among mCRC patients. In conclusion, REV1 expression levels and the REV1: c.2108G > A mutation may be related to cetuximab resistance in RAS wild-type mCRC.

Role of RNA N6-Methyladenosine Modification in Male Infertility and Genital System Tumors.

Epigenetic alterations, particularly RNA methylation, play a crucial role in many types of disease development and progression. Among them, N6-methyladenosine (m6A) is the most common epigenetic RNA modification, and its important roles are not only related to the occurrence, progression, and aggressiveness of tumors but also affect the progression of many non-tumor diseases. The biological effects of RNA m6A modification are dynamically and reversibly regulated by methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). This review summarized the current finding of the RNA m6A modification regulators in male infertility and genital system tumors and discussed the role and potential clinical application of the RNA m6A modification in spermatogenesis and male genital system tumors.

Development and validation of a novel prognostic nomogram including tumor deposits could better predict survival for colorectal cancer: a population-based study.

BACKGROUND: The number of tumor deposits (TDs) in colorectal cancer (CRC) prognosis remains debated. We evaluated whether the number of TDs affects prognosis in stage III CRC patients. METHODS: Univariate and multivariate analyses were performed with Cox proportional hazards models. The Kaplan-Meier method was used to estimate survival curves. The best cutoff was determined using X-Tile. Patients were 1:1 randomly divided into the training set or the testing set. Prognostic nomogram was established for stage III CRC patients. Concordance index (C-index) and calibration plot were used to assess Nomogram models. RESULTS: In total, 18,043 (84.69%) CRC patients without TDs and 3,263 (15.31%) patients with TDs were analyzed. Patients with TDs had significantly worse cancer-specific survival (CSS) rates (P<0.001). The number of TDs is an independent factor for the CSS of stage III CRC patients. CSS nomogram of stage III CRC patients was constructed based on race, age at diagnosis, tumor location, histological grade, pathological type, T, N, TDs, chemotherapy. In training set, C-index for CSS nomogram 0.762 (95% CI: 0.752-0.772). In testing set, the C-index for CSS nomogram 0.759 (95% CI: 0.749-0.768). The quality of calibration plots of nomogram models was high. CONCLUSIONS: The presence of TDs is an independent risk prognostic factor for stage III CRC. The number of TDs had a high proportion of prognostic impact.

Hyperprogressive disease in patients receiving immune checkpoint inhibitors.

Hyperprogressive disease (HPD) is an unexpected response pattern observed in immune checkpoint therapy and associated with poor prognosis in several cancers. Such patients can't benefit from immunotherapy and even experience a rapid disease progression. At present, many researchers have explored the HPD phenomenon, but there is no consensual definition of HPD in different studies. The incidence of HPD is about 4%-29% in various tumors. Many studies demonstrated that HPD was associated with worse prognosis, but the mechanism of HPD has not yet been fully clarified. Predictive factors in patients with HPD before treatment is one of the keys to managing patients receiving immune checkpoint inhibitors. Some factors, such as MDM2/4 amplification, EGFR mutations, and old age may be risk factors for HPD, but the results are discordant in different studies. Performing imaging evaluation and biopsy as early as possible is the main method to avoid the iatrogenic injury of immunotherapy at present.

Diverse fragment lengths dismiss size selection for serum cell-free DNA: a comparative study of serum and plasma samples.

Background: The objective of this study was to determine the features of fragment length for circulating cell-free DNA (cfDNA) from plasma and serum samples. Methods: Plasma and serum samples from different sources were randomly collected. Circulating cfDNA was extracted and purified by a precipitation-enriched and spin-column-based kit. The concentration of the purified DNA was immediately measured by a highly sensitive dsDNA quantitative assay, and then the fragment length was analyzed by capillary electrophoresis. The abundance of a specific fragment was estimated by the area under curve (AUC) for the fragment peak in the capillary electrophoresis. Results: A total of 199 plasma and 117 serum samples were extracted and analyzed. The average yield of cfDNA from the serum samples (131.67 ng/mL) was significantly higher than that from the plasma samples (32.78 ng/mL, p < 0.001). The average abundance of the 20-400 bp fragments in plasma cfDNA (84.4%) was significantly higher than that of serum cfDNA (51.9%, p < 0.001). Fragment peaks in serum cfDNA always presented in regions around 190 bp, 430 bp, and 630 bp, but plasma cfDNA generally showed a sharp peak in the 165-190 bp region and a much lower peak in the 300

Successful treatment of metastatic colorectal cancer with synchronous BRAF V600E mutation and dMMR with BGB-A317.

Metastatic colorectal cancer with BRAF mutation is a type of highly invasive malignant tumor with poor prognosis and few treatment options. Here, we report a case of a BRAF-mutant and DNA mismatch-repair deficiency colorectal cancer patient with postoperative recurrence as well as abdominal cavity and pelvic metastasis, whose condition was relieved continuously after treatment with a new anti-PD-1 antibody, BGB-A317.

Preclinical rationale and clinical efficacy of antiangiogenic therapy and immune checkpoint blockade combination therapy in urogenital tumors.

PURPOSE: In recent years, immune checkpoint blockade (ICB) therapies have shown good clinical responses in various solid cancers. However, a major challenge in the process of ICB treatment is when tumors do not have enough infiltrating T cells. Antiangiogenic drugs targeting vascular endothelial growth factor (VEGF) and its receptors have been approved for the treatment of various malignant solid tumors alone or in combination with other therapies. Our review mainly discusses the preclinical rationale and clinical efficacy of antiangiogenic and ICB combination therapy in urogenital tumors. METHODS: We reviewed relevant literature on preclinical research and clinical trial results regarding antiangiogenic and ICB combination therapy in urogenital tumors from PubMed. In addition, we searched ongoing clinical trials on ClinicalTrials.gov to collect information related to this specific topic. RESULTS: Antiangiogenesis therapy could enhance T cell recruitment and increase T cell infiltration into the tumor microenvironment by blocking VEGF-VEGF receptor 2 binding and downstream signaling pathways to normalize tumor blood vessels. The combination of ICB and antiangiogenesis therapy could improve antitumor activity according to subsequent preclinical experiments and several phase I/II/III clinical trials on urogenital tumors. CONCLUSION: Combined therapy has shown some antitumor efficacy in several urogenital tumors, such as metastatic renal cell carcinoma, metastatic urothelial and genitourinary tumors, endometrial carcinoma, ovarian cancer, and fallopian tube cancer. Combination therapy is a promising strategy that can be used to improve the therapeutic efficacy, and the identification of precise biomarkers of this combined therapy is the direction of future studies.

Zyxin as a potential cancer prognostic marker promotes the proliferation and metastasis of colorectal cancer cells.

Colorectal cancer (CRC) is a leading cause of cancer death. This study was conducted to investigate the functions and mechanisms of Zyxin (ZYX) in CRC. Multiomics analysis associated ZYX with CRC metastasis. ZYX expression levels were increased in human CRC tissues and related to shorter recurrence-free survival. Knockdown of ZYX expression resulted in inhibition of cell growth, invasion, and migration in vitro and in vivo. Comprehensive analysis of gene microarray analysis showed that ZYX may activate the pathway of NUPR1 and JNK, inhibit CST5, regulate focal adhesion (FA), and affect epithelial-mesenchymal transition in CRC cells. Results of gene microarray and membrane protein isobaric tags with relative and absolute quantitation labeling mass spectrometry found ten differentially expressed genes, which were associated with ZYX activity. Furthermore, real-time polymerase chain reaction was used to validate the expression patterns of selected genes in the integrative analysis. Taken together, our findings provide the first evidence that decreased expression level of ZYX impairs CRC cell proliferation and metastasis probably via the FA pathway.

Afatinib treatment for her-2 amplified metastatic colorectal cancer based on patient-derived xenograft models and next generation sequencing.

BACKGROUND: Substantial progress has been made in metastatic colorectal cancer (mCRC) treatment, but there is still a fraction of patients cannot find any effective therapeutic strategy after guideline-recommended standard chemotherapy and molecular targeted therapy. CASE PRESENTATION: Here we present a KRAS/NRAS/BRAF wild-type mCRC patient who has been previously treated with FOLFIRI (fluorouracil, leucovorin, and irinotecan), XELOX (capecitabine and oxaliplatin), cetuximab and bevacizumab, and then received the next generation sequencing (NGS) and whose metastatic subcutaneous nodule was resected to generate patient-derived xenograft (PDX) models. The NGS revealed HER-2 amplification as well as an activating mutation S310F and PDX models tested several drugs finding that afatinib was the optimal agent with notable efficacy and well tolerance among 6 regimens. Therefore, this patient started to take afatinib orally and achieved 3 months progression-free survival (PFS) and relief of clinical symptoms without severe adverse effects. CONCLUSIONS: NGS and PDX models have great significance for precision and individualized medicine in the mCRC treatment, especially for patients whose diseases have been progressed after multiline standard therapies.