Immunotherapy-induced pseudomembranous colitis (PMC) is an uncommon but increasingly recognized adverse effect of immune checkpoint inhibitors, particularly in patients with advanced malignancies. We present a case of a 68-year-old male with gastric adenocarcinoma undergoing treatment with immunotherapy and chemotherapy, who developed symptoms of PMC. Workup for Clostridium difficile and other common etiologies was negative. Colonoscopy revealed severe mucosal congestion and yellowish-green exudates, consistent with PMC. Based on the biopsy results and clinical presentation, after excluding common etiologies, immunotherapy-induced PMC was suspected. The patient responded to steroid therapy, with gradual improvement and a tapering regimen upon discharge. This case underscores the diagnostic challenges in identifying the etiology of PMC, particularly when it presents with diffuse involvement of the colon, which is an uncommon presentation for immunotherapy-related colitis. The overlap in clinical, endoscopic, and histopathological findings with other forms of colitis, such as Clostridium difficile infection (CDI) and inflammatory bowel disease, highlights the need for heightened awareness among clinicians. This case highlights the diagnostic challenges in recognizing immunotherapy-induced PMC, particularly with atypical, diffuse colonic involvement. The overlapping features with other colitis make timely diagnosis difficult. Further research is needed to refine diagnostic criteria and management strategies for immunotherapy induced colitis (IMC).

We developed a novel FTY720 prodrug (pro-FTY) that specifically inhibits sphingosine-1-phosphate signaling in cancer cells using a novel drug delivery system that reacts with acrolein. Our objective was to evaluate the efficacy and safety of pro-FTY in preclinical experiments. Ten breast cancer cell lines, two multidrug-resistant cell lines, and one normal mammary cell line were used to compare the IC50 values of pro-FTY with those of other drugs. Patient-derived organoids (PDO) were established and utilized for IC50 value comparisons. Drug efficacy was tested in mice bearing either syngeneic 4T1 cell tumors or patient-derived xenograft tumors, and blood analysis (including mass spectrometry) was performed. FTY720 and pro-FTY inhibited the survival of all breast cancer cell lines, including multidrug-resistant cells resistant to paclitaxel or doxorubicin. Unlike pro-FTY, FTY720 inhibited the survival of normal breast cell lines, suggesting that pro-FTY does not affect normal breast cells. Pro-FTY showed reproducible activity against multidrug-resistant PDOs, whereas paclitaxel and doxorubicin did not. Mass spectrometric analysis of pro-FTY-treated mice showed that FTY720 accumulated in tumors but was barely detectable in blood. Importantly, lymphocytopenia occurred in FTY720-treated mice but not in pro-FTY-treated mice. Furthermore, intravenous pro-FTY treatment significantly suppressed tumor growth in mice bearing patient-derived xenograft tumors generated from multidrug-resistant PDOs. In conclusion, pro-FTY inhibited breast cancer, including multidrug-resistant breast cancer, while avoiding lymphocytopenia, highlighting its clinical potential.

A series of six novel cyanopyridine derivatives bearing a 1,3,4-oxadiazole ring have been synthesized and characterized by FTIR, 13C NMR, 1H NMR, and elemental analysis. DFT calculations were carried out to determine their molecular geometries, electronic properties, and chemical reactivity. Their cytotoxicity has been evaluated against MCF-7 and CaCo-2 human cancer cell lines using the MTT assay. Most compounds displayed poor cytotoxic activity against the MCF-7 cell line except for compound 4e, which showed potent activity with IC50 = 8.352 µM. However, the CaCo-2 cell line was highly sensitive toward most tested compounds with an IC50 range from 2.612 µM to 8.394 µM except for compound 4 d. Molecular docking studies targeting human topoisomerase-IIβ revealed that all compounds exhibited excellent binding affinity within the enzyme's active site, with binding energies ranging from -7.33 to -8.28 kcal/mol. These findings suggest a potential anticancer mechanism underlying the observed cytotoxic activities. All tested compounds revealed low antioxidant activity in the DPPH assay. However, compounds 5b and 5 d presented moderate metal chelating activity. These findings underscore the potential anticancer properties of the synthesized cyanopyridine derivatives.

Menin inhibitors, which target the KMT2A-menin protein-protein interaction to inhibit blasts proliferation and induce differentiation, have demonstrated potential effects on acute leukemia subtypes characterized by overexpression of HOXA gene cluster and MEIS1 (including KMT2A rearrangements, NPM1 mutations, NUP98 rearrangements and other genetic alterations). Following the promising outcomes of the two pioneering menin inhibitors, revumenib and ziftomenib, other menin inhibitors, including bleximenib, enzomenib, BN-104 and HMPL-506 are currently under investigation in clinical trials. Several trials presented their initial outcomes at the 2024 ASH Annual Meeting. This review highlights the key outcomes of these pivotal clinical trials.

Microtubules and nuclear transmembrane SUN1/2 proteins promote the mobility of DNA Double Strand Breaks (DSBs) induced by ionizing radiation and the misrepair of one-ended DSBs induced in BRCA1-deficient cells by Poly(ADP-ribose) polymerase inhibitors (PARPi). However, whether microtubules promote aberrant DSBs repair by altering the nuclear structure and whether the nuclear structure itself plays a role in these processes is still unclear. Here we show that microtubule-dependent DSBs mobility in BRCA1-deficient cells after PARPi treatment is associated with nuclear envelope (NE) invaginations. Furthermore, increasing NE invaginations by Lmna deletion or inhibition of sphingolipid synthesis increases DSBs mobility, chromosomal aberrations, and PARPi cytotoxicity in BRCA1-deficient cells. These findings reveal a functional connection between the NE and DSB repair and suggest that drugs increasing NE deformability will enhance PARPi therapy efficacy in BRCA1-deficient cancers.

Linperlisib is a highly selective small-molecule inhibitor of phosphatidylinositol-3-kinase delta for the treatment of relapsed/refractory follicular lymphoma.

Cisplatin is a widely used chemotherapeutic drug for various cancers. One of the common adverse effects of cisplatin is nephrotoxicity including acute kidney injury (AKI) and acute kidney disease (AKD). Single Nucleotide Polymorphisms (SNPs) can be used to identify cancer patients who are susceptible to developing cisplatin-induced nephrotoxicity (CIN). In this study, we validated the association between 6 SNPs in the drug metabolizing enzyme genes, SLC22A2 (rs316019) & EPHX1 (rs1051740), and the DNA repair genes, ERCC1 (rs11615 & rs3212986) & ERCC2 (rs13181 & rs1799793), and CIN in the 169 Thai patients with head and neck, lung, or esophageal cancer. Effect of these SNPs on cumulative incidence of AKD, progression-free survival (PFS), and overall survival (OS) was also assessed. EPHX1 rs1051740 TC genotype was significantly associated with AKD in co-dominant [OR 2.894, 95% CI 1.091-7.680; P = 0.033] and over-dominant [OR 2.793, 95% CI 1.333-5.851; P = 0.006] models, and with an increased cumulative incidence of AKD (P = 0.021). Additionally, ERCC2 rs13181 and rs1799793 were significantly associated with OS (P = 0.002 and 0.004). Our results reveal an association between EPHX1 rs1051740 and AKD, and confirms the previously reported associations between ERCC2 SNPs and OS. These findings may help in predicting CIN in Thai cancer patients.

PurposeTo comprehensively evaluate the efficacy and safety of combining poly (ADP-ribose) polymerase (PARP) inhibitors with chemotherapy in patients with advanced breast cancer.MethodsA systematic literature search was conducted in PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov to identify randomized controlled trials (RCTs) evaluating PARP inhibitor-chemotherapy combinations. Studies reporting progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety outcomes were included. Data extraction and quality assessment were performed independently by two reviewers, and a meta-analysis was conducted using random-effects models.ResultsOf 970 studies retrieved, four RCTs involving 1064 patients met the inclusion criteria. PARP inhibitors combined with chemotherapy significantly improved PFS (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.63-0.84, P < .0001) and showed a trend towards improved OS (HR 0.93, 95% CI 0.79-1.09, P = .36), though this was not statistically significant. There was no significant improvement in ORR (RR 1.08, 95% CI 0.98-1.20, P = .13). Regarding safety, no significant difference was observed in all grades or grade 3-4 adverse events (AEs) overall, but the combination therapy was associated with an increased risk of anemia, nausea, and diarrhea (RRs ranging from 1.14 to 1.29, all P < .01).ConclusionPARP inhibitor combined with chemotherapy is an effective option for the treatment of patients with advanced breast cancer, but its potential increased risks of specific AEs need to be weighed. Clinicians should make individualized treatment plans according to the specific conditions of patients, comprehensive consideration of efficacy and safety.

Envafolimab is a novel immune checkpoint inhibitor (ICI) with several advantages due to its subcutaneous administration. Phases I and II randomized controlled trials have demonstrated promising efficacy in treating colorectal and gastric cancer. However, the safety and efficacy of Envafolimab in patients with advanced lung cancer remain to be investigated.

Breast cancer as a "cold" tumor presents an immunosuppressive microenvironment and inferior T-lymphocyte infiltration, leading to poor efficacy of immune checkpoint blockade (ICB) therapies. It is urgent to develop new effective combination treatment strategies. Pyroptosis is an inflammatory form of programmed cell death mediated by Caspase-1/GSDMD pathway, which can cause immunogenic cell death (ICD) and boost the immunogenicity of tumor. In this study, an immune activator (siRNAPD-L1@HA-ZIF-8) was proposed based on metal-organic framework (ZIF-8) nanosystem carrying Zn2+ and PD-L1 siRNA to improve anti-tumor immunotherapy through evoking pyroptosis combined with immune checkpoint blockade. We found that siRNAPD-L1@HA-ZIF-8 could disintegrate under low pH and release massive amounts of Zn2+, leading to elevated intracellular osmolarity and ROS, eventually resulting in pyroptosis. Zn2+ overload-triggered pyroptosis caused ICD effect and promoted the maturation of dendritic cells and infiltration of T-lymphocytes, which reprogramed the immunoecology of tumor from "cold" to "hot" state. Meanwhile, the co-delivered PD-L1 siRNA decreased the expression of PD-L1 protein on the tumor surface, relieving immune evasion and recovering the recognition and killing ability of cytotoxic T-lymphocytes, further boosting the immune response. This research not only confirmed the potential of ZIF-8 intrinsically as an immune activator that induces pyroptosis in combination with encapsulated PD-L1 siRNA-mediated ICB therapy for the first time, but also adequately revealed the immune responses mechanism by multiple techniques. This study will provide new strategies for pyroptosis-mediated treatments for augmented anti-tumor immunotherapy and greatly inspire the further development of immune activators based on Zn2+ overload-triggered pyroptotic pathway.

This study investigated the protective effects of verbascoside (VER) against 5-fluorouracil (5-FU)-induced gastrointestinal mucositis in Wistar albino rats.

Digestive system cancers, including esophageal, gastric, colorectal, pancreatic, hepatocellular, and biliary tract cancers, constitute a major global health challenge. Despite therapeutic advancements, prognosis remains poor, highlighting the urgent need for novel treatment strategies. We hypothesized that drug repositioning, facilitated by pan-cancer analyses, could lead to the identification of effective treatment strategies for these cancers.

Basal cell carcinoma (BCC) is a prevalent form of skin cancer that can be localized or metastatic. Current evidence supports the use of Hedgehog (Hh) pathway inhibitors for locally advanced or metastatic BCC with resistance due to genetic alterations in the Hh pathway. This systematic review evaluated the prevalence of genetic alterations in Hh pathway genes in BCC.

Improved treatment strategies for HPV-positive cancers are urgently required. The viral E6/E7 oncoproteins are essential for the proliferation of HPV-positive cancer cells and considered attractive therapeutic targets. Metformin is proposed to be repurposed for cancer therapy, but this is under controversial debate. We previously demonstrated that E6/E7 expression and the proliferation of HPV-positive cancer cells are repressed by Metformin. Here, we explore the effects of Metformin on the phenotype of HPV-positive cancer cells in detail, either applied as monotreatment or in combination with chemotherapeutic agents. We provide evidence that the downregulation of E6/E7 is not the primary mechanism underlying Metformin's growth-inhibitory effect in HPV-positive cancer cells. Specifically, compared to targeted E6/E7 repression by RNA interference (RNAi), Metformin treatment differently altered the expression of growth regulatory proteins, exerted different effects on the cell cycle, and was able to suppress growth even in the presence of E6/E7. Furthermore, we found that cancer cells pre-treated with Metformin become resistant to senescence induction by the pro-senescent chemotherapeutic agent Etoposide, likely as a secondary effect of Metformin-induced growth inhibition. Finally, depending on experimental conditions, we uncover divergent, even opposing, effects on the proliferation of HPV-positive cancer cells when Metformin is combined with Cisplatin, with p53 playing a key role in these processes. Collectively, our results show that Metformin exerts complex effects on the phenotype of HPV-positive cancer cells, which are critically influenced by experimental conditions. Our findings may also explain the discrepant results in the literature, reporting agonistic or antagonistic effects upon combining Metformin with Cisplatin.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness and safety of immune checkpoint inhibitors (ICIs) for people with advanced, unresectable or metastatic oesophageal cancer.

The premetastatic niche (PMN) represents a metastasis-facilitative microenvironment established prior to tumor dissemination, initiated by vascular leakage and endothelial cell (EC) functional remodeling. ECs play pivotal roles as bridges in different stages of the metastatic cascade. As critical stromal components within the PMN, ECs not only drive angiogenesis but also actively orchestrate immune suppression, extracellular matrix (ECM) remodeling, and the inflammatory signaling characteristic of PMN formation, with multiple specific signaling pathways such as VEGF/Notch playing a crucial role. With the evolving understanding of the role of ECs in controlling tumor metastasis, therapeutic strategies targeting ECs within the PMN, such as antiangiogenic therapy (AAT), targeting of endothelial glycocalyx (GCX), inhibition of tumor-derived exosome (TDE) and angiocrine signaling, are becoming research hotspots. This review systematically delineates the cellular and molecular composition of PMNs, dynamically dissects their spatiotemporal evolution, and highlights organ-specific mechanisms of EC-driven PMN establishment. Furthermore, we summarize emerging EC-targeted therapeutic strategies, providing innovative insights for inhibiting tumor metastasis.

This study aims to evaluate the efficacy and safety of anlotinib combined with immune checkpoint inhibitors (ICIs) in patients with previously immunotherapy-treated extensive-stage small cell lung cancer (ES-SCLC).

Cholangiocarcinoma (CCA) is an aggressive, heterogeneous malignancy with limited effective treatment options. One of the key epigenetic dysregulations in CCA is aberrant DNA hypermethylation, suggesting that targeted DNA methylation is a promising therapeutic strategy for this disease. However, there is still limited information on how effective DNA demethylating agents are in the treatment of CCA in the clinical setting, and further studies are urgently needed to evaluate their potential benefits. Here, we established four patient-derived CCA cell lines and demonstrated that the DNA methyltransferase (DMNT) inhibitors decitabine and azacitidine had minimal effects on inhibiting CCA proliferation. A combinatorial drug screen identified PARP inhibitors as sensitizers that synergistically enhanced the antitumor effects of decitabine. The combination of DNMT inhibitors and PARP inhibitors therapeutically inhibited the growth of CCA cancers in multiple in vitro cancer cell lines and organoid models, as well as in vivo cell line-derived xenografts, patient-derived xenograft models, and CCA in mice induced by hydrodynamic tail vein injection. Mechanistically, transcriptomic profiling analysis showed that combination treatment activated the inflammatory signaling pathway and suppressed the cell cycle-related pathways in CCA. In addition, the combination synergistically induced DNA damage and cellular senescence of CCA cancer cells. Together, our study provides a preclinical proof-of-concept for the use of DNMT inhibitors in combination with PARP inhibitors as a novel therapeutic strategy and potentially optimizes current clinical practice in the treatment of CCA.

H. pylori infection is closely associated with the tumor microenvironment (TME) in gastric cancer (GC), yet its underlying mechanism is elusive. Hence, it is imperative to explore the microenvironment and drug resistance arising from H. pylori to enhance therapeutic strategies for GC.

This investigation seeks to examine the association between spleen volume and prognosis in cancer patients undergoing immune checkpoint inhibitor (ICI) treatment.