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Abstract Background Limited data have been used to evaluate the efficacy of immunotherapy in metastatic colorectal cancer (mCRC). Furthermore, potential markers that can be used to identify responding patients and to further improve efficacy have not been fully explored. Methods and Results In our study, we included a total of 97 patients with mCRC, who each received programmed death‐1 (PD‐1) inhibitor‐based combination therapy at our center. All 12 hypermutated patients benefited from immunotherapy, with median progression‐free survival (mPFS) reaching 28.3 months, regardless of liver metastasis. The objective response rate (ORR) of non‐hypermutated patients was 16.5% (14/85), with an mPFS of 4.0 months. For non‐hypermutated patients, multivariate analysis revealed that the combination of liver metastasis and baseline lesion number significantly stratified response and survival. The lesion‐based analysis indicated that the lymph node was the most responsive, followed by the peritoneum and lung, with liver metastasis being the least responsive. None of the patients (0/7) with negative programmed ligand‐1 (PD‐L1) expression responded, and positive PD‐L1 expression may serve as a biomarker (mPFS 5.7 vs. 2.2 months, p = 0.002) that can be used to further guide treatment in non‐hypermutated mCRC with liver metastasis (CRLMs). Conclusion Patients with hypermutated mCRC benefited significantly from immunotherapy, whereas the non‐hypermutated cohort with liver metastasis and numerous lesions showed less benefit. The lesion sites reflected varying levels of efficacy, among which PD‐L1 potentially cooperated to guide the immunotherapy of CRLMs.

Background: Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Methods: Between March 2017 and September 2022, the patients diagnosed as stages I–IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan–Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. Results: A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS /BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36–5.12; p = 0.0091). Conclusion: In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I–III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

Abstract Background Circulating soluble programmed death ligand 1 (sPD-L1) can negatively regulate T-cell function and serve as a prognostic or predictive marker in a variety of cancers. However, rare studies have evaluated the potential roles of sPD-L1, and no study has estimated its predictive value for the efficacy of immune treatment in colorectal cancer (CRC). Methods Plasma samples from 192 CRC patients were used to estimate correlations between clinicopathological features and sPD-L1, secreted PD-L1 (secPD-L1) and exosomal PD-L1 (exoPD-L1). Baseline and posttreatment sPD-L1 levels were also investigated in 55 patients with metastatic CRC (mCRC) treated with chemotherapy ± targeted therapy and 40 patients with proficient mismatch repair (pMMR) mCRC treated with combination immunotherapy. Both sPD-L1 and secPD-L1 were quantified by enzyme-linked immunosorbent assay, while exoPD-L1 was analyzed using flow cytometry. Results secPD-L1 was the major component and positively correlated with sPD-L1 in CRC, while exoPD-L1 was almost undetectable. Higher levels of sPD-L1 were detected in patients with distant metastasis, especially those with distant lymph node metastasis and tissue combined positive score (CPS) instead of tumor proportion score (TPS). Chemotherapy or targeted therapy did not significantly impact sPD-L1 concentration. Progressive disease on combination immunotherapy was associated with an increase in sPD-L1 level, whereas no significant change was observed in patients with durable clinical benefit. Conclusion sPD-L1 mainly consisted of secPD-L1, and its level was higher in patients with distant metastasis, especially distant lymph node metastasis and positive CPS. sPD-L1 is a potential dynamic marker to identify rapid progression on combination immunotherapy and avoid ineffective treatment for pMMR CRC.

ObjectControversy remains regarding the safety and efficacy of hemorrhoid ligation and stapled hemorrhoidopexy (SH) in the treatment of hemorrhoids. The study was to explore the operative outcomes of patients underwent multiple thread ligations (MTL) with SH for the management of grade III hemorrhoids.MethodsThis cohort study included patients who underwent MTL (MTL group, 128 cases) or SH (SH group, 141 cases) for grade III hemorrhoids between June 2019 and May 2021. A total of 115 patients in MTL group and 115 patients in SH group were finally included by propensity score matching with a ratio of 1:1. The primary outcome was the recurrence of prolapse within 6 months. Secondary outcomes were operative time, post-operative pain scores, hospital stay, the incidence of complications, Wexner incontinence score, and quality of life of patients with constipation at 6 months post procedure.ResultsMultiple thread ligations and SH resulted in comparable recurrence within 6 months of follow-up, with five and seven cases of recurrence, respectively, (P = 0.352). The two groups had comparable outcomes in terms of post-operative pain, hospital stay, Wexner incontinence scores, and constipation-related quality of life (all P > 0.05). The median operative time was 16 min (15–18 min) in the MTL group versus 25 min (16–33 min) in the SH group (P < 0.01). Univariate analysis showed that the MTL technique had a lower risk of postoperative bleeding than that with the SH technique (P < 0.05).ConclusionThe study indicated that the MTL technique might achieve comparable operative outcomes compared with the SH technique for the management of grade III hemorrhoids, nevertheless, MTL seemed to be associated with less risk of surgical bleeding than SH.

The natriuretic peptide family (NPs) is a group of natural endocrine hormones, containing a 17-amino acid ring structure connected by disulfide bonds of two cysteines. In this review, the members of the natriuretic peptide family and their corresponding receptors as well as the anti-cancer effects are introduced. Four cardiac hormones of NPs (ANP, VD, KP and LANP) can effectively inhibit the growth of human small cell lung cancer, breast cancer and other tumors and significantly reduce tumor volume in vivo. The in vitro experiments also show that cardiac hormones, CNP and urodilatin can effectively inhibit the growth of most tumor cells. We then further summarized the anti-cancer mechanism of natriuretic peptides. Finally, we introduce several methods that modify natriuretic peptides, leading to enhance their stability and prolong the biological effects of these peptides, which might be helpful for the clinical application in the future. Peptide therapy is a very promising field for cancer treatments since they can induce the death of cancer cells without dramatically affecting normal cells. The synthesis of a useful and stable natriuretic peptide can enhance the effect of cancer treatments and significantly reduce drug resistance and toxicity.

IntroductionTargetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study.MethodsAmong 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively.ResultsBRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p

Long interspersed nuclear element 1 (LINE-1) is a dominant autonomous retrotransposon in human genomes which plays a role in affecting the structure and function of somatic genomes, resulting in human disorders including genetic disease and cancer. LINE-1 encoded ORF1p protein which possesses RNA-binding and nucleic acid chaperone activity, and interacts with LINE-1 RNA to form a ribonucleoprotein particle (RNP). ORF1p can be detected in many kinds of tumors and its overexpression has been regarded as a hallmark of histologically aggressive cancers. In this study, we developed an In-Cell Western (ICW) assay in T47D cells to screen the compounds which can decrease the expression of ORF1p. Using this assay, we screened 1,947 compounds from the natural products library of Target Mol and Selleckchem, among which three compounds, Hydroxyprogesterone, 2,2':5′,2″-Terthiophene and Ethynyl estradiol displayed potency in diminishing LINE-1 ORF1p expression level. Further mechanistic studies indicated the compounds act by affecting LINE-1 RNA transcription. Notably, we demonstrated that the compounds have an inhibitory effect on the proliferation of several lung and breast cancer cell lines. Taken together, we established a high throughput screening system for ORF1p expression inhibitors and the identified compounds provide some clues to the development of a novel anti-tumor therapeutic strategy by targeting ORF1p.

The development of simple and probe-integrated aptamer sensors for the electrochemical detection of tumor biomarkers is of great significance for the diagnosis of tumors and evaluation of prognosis. In this work, a probe-integrated aptamer sensor is demonstrated based on the stable confinement of an electrochemical probe in a bipolar nanochannel film, which can realize the reagentless electrochemical detection of the tumor biomarker carcinoembryonic antigen (CEA). To realize the stable immobilization of a large amount of the cationic electrochemical probe methylene blue (MB), a two-layer silica nanochannel array (SNF) with asymmetric charge was grown on the supporting electrode from bipolar SNF (bp-SNF). The inner SNF is negatively charged (n-SNF), and the outer-layer SNF is positively charged (p-SNF). The dual electrostatic interaction including the electrostatic adsorption from n-SNF and the electrostatic repulsion from p-SNF achieve the stable confinement of MB in bp-SNF. The recognitive interface is fabricated by the covalent immobilization of the CEA aptamer on the outer surface of bp-SNF, followed by the blocking of non-specific binding sites. Owing to the stable and abundant immobilized probes and highly specific aptamer interface, the developed aptamer sensor enables the sensitive detection of CEA in the range of 1 pg/mL to 1 μg/mL with a low limit of detection (LOD, 0.22 pg/mL, S/N = 3). Owing to the high selectivity and stability of the developed biosensor, reagentless electrochemical detection of CEA in serum was realized.

KRAS gene mutation is widespread in tumors and plays an important role in various malignancies. Targeting KRAS mutations is regarded as the “holy grail” of targeted cancer therapies. Recently, multiple strategies, including covalent binding strategy, targeted protein degradation strategy, targeting protein and protein interaction strategy, salt bridge strategy, and multivalent strategy, have been adopted to develop KRAS direct inhibitors for anti-cancer therapy. Various KRAS-directed inhibitors have been developed, including the FDA-approved drugs sotorasib and adagrasib, KRAS-G12D inhibitor MRTX1133, and KRAS-G12V inhibitor JAB-23000, etc. The different strategies greatly promote the development of KRAS inhibitors. Herein, the strategies are summarized, which would shed light on the drug discovery for both KRAS and other “undruggable” targets.

Cryptic species comprise two or more taxa that are grounded under a single name because they are more-or-less indistinguishable morphologically. These species are potentially important for detailed assessments of biodiversity, but there now appear to be many more cryptic species than previously estimated. One taxonomic group likely to contain many cryptic species is Dicranopteris, a genus of forked ferns that occurs commonly along roadsides in Asia. The genus has a complex taxonomical history, and D. linearis has been particularly challenging with many intra-specific taxa dubiously erected to accommodate morphological variation that lacks clear discontinuities. To resolve species boundaries within Dicranopteris, we applied a molecular phylogenetic approach as complementary to morphology. Specifically, we used five chloroplast gene regions (rbcL, atpB, rps4, matK, and trnL-trnF) to generate a well-resolved phylogeny based on 37 samples representing 13 taxa of Dicranopteris, spanning the major distributional area in Asia. The results showed that Dicranopteris consists of ten highly supported clades, and D. linearis is polyphyletic, suggesting cryptic diversity within the species. Further through morphological comparison, we certainly erected Dicranopteris austrosinensis Y.H. Yan & Z.Y. Wei sp. nov. and Dicranopteris baliensis Y.H. Yan & Z.Y. Wei sp. nov. as distinct species and proposed five new combinations. We also inferred that the extant diversity of the genus Dicranopteris may result from relatively recent diversification in the Miocene based on divergence time dating. Overall, our study not only provided additional insights on the Gleicheniaceae tree of life, but also served as a case of integrating molecular and morphological approaches to elucidate cryptic diversity in taxonomically difficult groups.

Tumor-specific CD8+T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8+T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8+T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.

Background: This study was designed to compare the long-term surgical outcomes of patients with mid and low rectal cancer after open or hand-assisted laparoscopic surgery (HALS). Methods: A case-matched controlled prospective analysis of 116 patients who underwent hand-assisted laparoscopic surgery (HALS) for stage I to III mid and low rectal cancer from 2005 to 2010 was performed. Contemporary patients who underwent open rectal surgery were matched to the HALS group at the ratio of 1:1. The perioperative clinical outcomes, postoperative pathology, and survival outcomes were compared between the groups. Results: The patient characteristics between the two groups were comparable. Ninety patients in the open group and 85 in the HALS group received sphincter-preserving surgery. HALS resulted in less blood loss and wound infection, faster return to oral diet, shorter postoperative hospital stay, and longer operating time. The two groups had similar complication rates. Lymph node retrieval and involvement of circumferential and distal margins were similar for both procedures. Cumulative incidences of locoregional recurrence, disease-free, or overall survival rates were statistically similar. Conclusions: This study suggests that HALS for mid and low rectal cancer is acceptable in terms of short-term clinical outcomes and long-term survival results. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the most common cause of cancer death worldwide. Numerous studies have identified the roles of survivin -31 G/C and angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms in CRC risk; however, the results remain inconclusive. This study was to investigate associations between these two polymorphisms and CRC susceptibility. Methods: A comprehensive literature search was conducted to collect relevant case-control studies published between 2000 and 2014. The extracted data were statistically analyzed, and the odds ratios (ORs) with 95% confidence intervals (CIs) were employed to estimate the strength of association. Results: A total of 11 studies were included in the meta-analysis. For survivin G/C polymorphism, six articles reported 1,840 cases and 1,804 controls. Overall, we found the frequency of C allele is higher in CRC cases than that in the healthy controls (57.2% vs. 48.0%), and C allele significantly increased the risk of CRC compared to G allele in allele model (OR = 1.46, 95% CI = 1.33-1.60, P < 0.00001). This association was also found in other genetic models (P < 0.00001). Stratified analysis by ethnicity showed significant association in each genetic model among the Asian population. For ACE I/D polymorphism, five studies included 758 cases and 6,755 controls. No significant association was found in any genetic models. Conclusions: Our results showed that survivin -31 G/C polymorphism might contribute to risk of CRC, especially in the Asian populations. However, the ACE I/D polymorphism is not a genetic factor concerning the risk for CRC. More studies with larger sample sizes are required in the future. [ABSTRACT FROM AUTHOR]