A growing body of research indicates that it contributes to cancer cell resistance to glucose deficiency, a typical feature of malignant tissues. Current research into the mechanisms by which extracellular lactate and acidosis, acting as both enzymatic inhibitors and metabolic signals, influence the transition of cancer cell metabolism from the Warburg effect to an oxidative state is discussed. This adaptive metabolic shift enables cancer cells to withstand glucose scarcity, making lactic acidosis a promising new target for anticancer therapies. We delve into how to incorporate findings on the effects of lactic acidosis on tumor metabolism, and discuss the resulting implications for future research.
The potency of drugs that disrupt glucose metabolism, specifically glucose transporters (GLUT) and nicotinamide phosphoribosyltransferase (NAMPT), was investigated in neuroendocrine tumor (NET) cell lines (BON-1 and QPG-1) and small cell lung cancer (SCLC) cell lines (GLC-2 and GLC-36). The significant impact of GLUT inhibitors, fasentin and WZB1127, and NAMPT inhibitors, GMX1778 and STF-31, on the proliferation and survival of tumor cells is evident. Despite the presence of NAPRT in two NET cell lines, NAMPT inhibitor-treated NET cell lines could not be rescued using nicotinic acid (via the Preiss-Handler salvage pathway). The specificity of GMX1778 and STF-31 in the context of glucose uptake within NET cells was eventually determined through our analysis. In preceding experiments involving STF-31 and a panel of NET-free tumor cell lines, both drugs displayed specific inhibition of glucose uptake at a higher concentration (50 µM), but not at a lower concentration (5 µM). The conclusions drawn from our data highlight GLUT inhibitors, and especially NAMPT inhibitors, as potential treatments for neuroendocrine tumors.
The malignancy esophageal adenocarcinoma (EAC) is characterized by a rising incidence, a poorly understood pathogenesis, and unacceptably low survival rates. Next-generation sequencing was employed for high-coverage sequencing of 164 EAC samples from untreated (by chemo-radiotherapy) naive patients. The entire cohort revealed 337 distinct variants, with TP53 emerging as the gene most frequently altered (6727%). Cancer-specific survival was demonstrably diminished in cases presenting with missense mutations within the TP53 gene, a finding supported by a statistically significant log-rank p-value of 0.0001. Seven instances of disruptive HNF1alpha mutations were found, co-occurring with modifications in the expression of other genes. In addition, gene fusions were identified via RNA massive parallel sequencing, suggesting their prevalence in EAC. In summary, our investigation has shown that a particular type of TP53 mutation, characterized by missense changes, is significantly correlated with worse cancer-specific survival in patients with EAC. Emerging research has revealed HNF1alpha to be a newly identified gene mutated in EAC cases.
The grim prognosis for glioblastoma (GBM), despite being the most common primary brain tumor, persists with the current treatment approaches. While immunotherapeutic approaches in GBM have proven somewhat ineffective thus far, recent innovations suggest a brighter future. ALKBH5 inhibitor 1 ic50 The procedure of chimeric antigen receptor (CAR) T-cell therapy, a noteworthy advance in immunotherapy, comprises the extraction of autologous T cells, their genetic engineering for the expression of a receptor specific for a GBM antigen, and their reintroduction into the patient. Promising preclinical results have emerged from numerous studies, leading to the clinical trial evaluation of several CAR T-cell therapies for the treatment of glioblastoma and other brain cancers. Positive results were seen in lymphoma and diffuse intrinsic pontine gliomas, yet initial data on glioblastoma multiforme revealed no demonstrable clinical benefit. One possible explanation for this is the limited availability of distinct antigens within glioblastoma, the variable expression profiles of these antigens, and the loss of these antigens after initiating antigen-specific therapies due to immune system adaptation. An overview of current preclinical and clinical research concerning CAR T-cell therapy in GBM is provided, together with possible approaches to engineer more effective CAR T-cells for this indication.
Background immune cells, upon penetrating the tumor microenvironment, discharge inflammatory cytokines, particularly interferons (IFNs), thus activating antitumor responses and furthering tumor removal. Although, current findings propose that, at times, cancerous cells can also utilize interferons to bolster development and survival. During normal physiological conditions, the nicotinamide phosphoribosyltransferase (NAMPT) gene, encoding the essential NAD+ salvage pathway enzyme, is expressed constantly in cells. Nonetheless, melanoma cells exhibit heightened energetic requirements and elevated NAMPT expression levels. ALKBH5 inhibitor 1 ic50 Our hypothesis is that interferon gamma (IFN) controls NAMPT expression in tumor cells, creating a resistance mechanism that mitigates the inherent anti-tumorigenic effects of interferon. Employing diverse melanoma cell lines, mouse models, CRISPR-Cas9 technology, and molecular biological approaches, we investigated the significance of interferon-induced NAMPT in melanoma progression. We have found that IFN's action on melanoma cells includes metabolic reprogramming driven by Nampt induction, possibly through a Stat1 binding site in the Nampt gene, thus improving cell proliferation and survival. IFN/STAT1-induced Nampt plays a crucial role in accelerating melanoma's development inside the body. Our findings underscore the direct influence of IFN on melanoma cells, leading to heightened NAMPT expression and amplified in vivo growth and viability. (Control group: n=36; SBS KO group: n=46). This discovery points to a possible therapeutic target, potentially increasing the efficacy of immunotherapies utilizing interferon responses in clinical applications.
We investigated variations in HER2 expression patterns comparing primary tumors to distant metastases, especially within the HER2-negative group of primary breast cancers (classifying as HER2-low and HER2-zero). The retrospective study encompassed 191 consecutively gathered sets of primary breast cancer specimens and their associated distant metastases, diagnosed between 1995 and 2019. The dataset of HER2-negative samples was divided into two subgroups: HER2-undetected (immunohistochemistry [IHC] score 0) and HER2-low-expressing (IHC score 1+ or 2+/in situ hybridization [ISH]-negative). A central objective was to ascertain the discordance rate in paired primary and metastatic tissue samples, with a specific emphasis on the site of secondary tumor development, molecular classification, and newly emerging metastatic breast cancer. ALKBH5 inhibitor 1 ic50 The relationship was established by means of cross-tabulation and the computation of Cohen's Kappa coefficient. The conclusive study group contained 148 sample sets. The HER2-low category encompassed the largest segment of the HER2-negative cohort, encompassing 614% (n = 78) of primary tumors and 735% (n = 86) of metastatic samples. In 63 cases, a 496% discordance rate was observed between the HER2 status of primary tumors and their distant metastases. The calculated Kappa value was -0.003, with a 95% confidence interval spanning from -0.15 to 0.15. The most frequent occurrence was the development of a HER2-low phenotype (n=52, 40.9%), mainly representing a transition from HER2-zero to HER2-low (n=34, 26.8%). Significant discrepancies in HER2 discordance were found to be correlated with variations in both metastatic sites and molecular subtypes. A notable disparity existed in HER2 discordance rates between primary and secondary metastatic breast cancer. Primary cases displayed a rate of 302% (Kappa 0.48, 95% confidence interval 0.27-0.69), while secondary cases presented with a rate of 505% (Kappa 0.14, 95% confidence interval -0.003-0.32). A critical evaluation of discordant therapeutic effects in the primary tumor and its corresponding metastases is vital, highlighting the need for such a nuanced analysis.
For the past decade, immunotherapy has led to a noteworthy advancement in the management of various forms of cancer. With the pivotal approvals of immune checkpoint inhibitors, new hurdles appeared in various clinical contexts. Responses to tumors aren't triggered by all tumor types, due to insufficient immunogenic properties. Likewise, the immune microenvironment within many tumors promotes evasion from immune detection, leading to resistance and, subsequently, restricting the persistence of any elicited responses. Bispecific T-cell engagers (BiTEs) and other emerging T-cell redirecting strategies are appealing and promising immunotherapeutic solutions for this limitation. This review delves into the current evidence surrounding BiTE therapies' applications in solid tumors, offering a comprehensive perspective. Despite the relatively limited efficacy of immunotherapy in advanced prostate cancer, this review analyses the biological basis and positive results associated with BiTE therapy, and suggests potential tumour-associated antigens that could be integrated into the design of future BiTE constructs. Our review's objective encompasses evaluating the advancements in BiTE therapies for prostate cancer, highlighting the key impediments and fundamental restrictions, and subsequently exploring prospective research trajectories.
Investigating the relationship between survival and perioperative outcomes in patients with upper tract urothelial carcinoma (UTUC) undergoing open, laparoscopic, and robotic radical nephroureterectomy (RNU).
A multi-institutional, retrospective analysis was performed on non-metastatic upper tract urothelial carcinoma (UTUC) patients undergoing radical nephroureterectomy (RNU) from 1990 to 2020. Missing data imputation was performed using the multiple imputation by chained equations method. Patients were categorized into three surgical treatment groups, followed by adjustment using 111 propensity score matching (PSM). For each group, the survival rates were calculated for recurrence-free survival (RFS), bladder recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS).