Alejandro Bravo-Cuellar

Pancreatic ductal adenocarcinoma (PDAC) is rarely detected before the disease is advanced, and existing serum markers are insufficient for early detection. Its systemic immune alterations are incompletely characterized and rarely examined by sex. We measured 19 serum cytokines by bead-based multiplex assay in 22 patients with PDAC and 16 controls, comparing groups overall and separately in women and men, and examined co-regulation among them. In the full cohort, interleukin-7 (IL-7) was the only cytokine to discriminate patients from controls after correction for multiple testing. Adjustment for age strengthened this association, and IL-7 matched the discrimination of carbohydrate antigen 19-9 (CA19-9). After stratification by sex, IL-7 remained the only cytokine higher in women, though it did not survive correction within that subgroup, whereas in men, eight innate, T-helper 17 (Th17) and type I interferon cytokines (IL-1α, IL-1RA, IL-31, IFN-α, IL-17A, IL-17F, TNF-α, and TNF-β) separated patients from controls, although the male control group was small. The correlation network present in controls was largely absent in patients, which instead showed few associations centered on IL-2, IL-5 and IL-6. These findings identify IL-7 as a candidate discriminator of PDAC and show that the cytokines separating patients from controls differed by sex, warranting validation in a larger, sex-balanced cohort that also measures sex hormones.

Background/Objectives: Differentiating between benign and malignant ovarian adnexal masses before surgery is a significant diagnostic challenge. This study examined a wide range of circulating plasma molecules (immune and inflammatory) to identify potential markers to classify tumors as benign or malignant. The goal was to develop a proof-of-concept tool for preoperative risk stratification. Methods: Twenty-three plasma molecules were evaluated in women with benign lesions (n = 68) and women with malignant ovarian tumors (n = 25). To evaluate the behavior of each marker in a normal population, women without adnexal pathology were also included (n = 11). The results were compared using the Kruskal–Wallis test with Dunn post hoc pairwise comparisons, the Benjamini–Hochberg correction for multiple comparisons, and ROC analysis. TGF-β isoforms and CA125 were measured in the complete cohort (n = 104), while the remaining molecules were assessed in a reduced cohort (n = 51). Two classification approaches were developed using TGF-β3 and IL-13: a sequential two-step algorithm and an ordinal logistic regression model. Apparent performance was corrected for optimism using Harrell’s bootstrap procedure. Results: Ten molecules reached statistical significance. Among the significant molecules, TGF-β3 identified ovarian lesions regardless of malignant status (AUC = 0.983), while IL-13 showed perfect malignancy-specific separation from benign cases (AUC = 1.000). Their combination in an ordinal logistic regression model produced three non-overlapping diagnostic strata across all three groups, significantly outperforming CA125, HE4, and ROMA at the malignancy-separation boundary (DeLong p < 0.05) in our exploratory cohort. Conclusions: TGF-β3 and IL-13 represent a biologically complementary marker pair whose combined ordinal regression model shows promising performance and warrants prospective validation in larger, multicenter independent cohorts as a preoperative risk-stratification tool for ovarian adnexal masses.

Coronavirus (CoV) disease 2019 (COVID‑19) deteriorates existing hepatopathies, such as liver cirrhosis and metabolic‑associated syndrome liver disease (MASLD), which in turn increases the risk of serious complications. The pathophysiology of COVID‑19 includes inflammation, proinflammatory cytokine storms, oxidative stress and fibrosis. Notably, pentoxifylline (PTX) blocks nuclear factor‑κB activity, thus inhibiting the secretion of proinflammatory cytokines, and is an antioxidant and antifibrotic agent. The present study reported on the use of PTX in 20 patients with liver cirrhosis (13 men, 7 women) of different etiologies and in 25 patients with MASLD (16 women, 9 men) infected with severe acute respiratory syndrome‑CoV‑2; age range of all patients, 29‑83 years. Firstly, the detection of CoV‑2 was confirmed by PCR. All patients received PTX (400 mg twice daily; per os) for 8 weeks, alongside standard care provided for COVID‑19 symptoms and for their liver condition. In all patients, the following inflammatory markers were assessed at the beginning and at the end of the study: C‑reactive protein, D‑dimer, ferritin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH), platelet count and oxygen saturation. Statistical analysis was performed using the Wilcoxon signed‑rank test. At the end of the study, no patient required admission to the intensive care unit and no patient fatalities were noted. Notable improvement was noted in seven of the eight inflammatory markers in both liver pathologies, and the only sole parameter that worsened was LDH. Notably, no serious adverse events were observed in these patients. In conclusion, PTX treatment was associated with favorable clinical outcomes and improved inflammatory marker levels in patients with liver cirrhosis and MASLD with COVID‑19.

Cancer is one of the leading causes of death worldwide. In cancer therapy, anti-cancer drugs are the current treatment-of-choice for patients with metastatic cancers, but these drugs present a major drawback: they destroy healthy cells along with cancerous cells. Unfortunately, the drug discovery process for de novo drugs is costly and time-consuming. To address this global problem, our research team has established the concept of “Chemotherapy with a molecular rational basis”, which focuses on the identification of molecular targets in tumor cells, whose activation or inhibition induces apoptosis or sensitizes the tumor cells to apoptosis. Here we review the experimental and clinical evidence of pentoxifylline (PTX) in the setting of chemotherapy with a molecular rational basis. A search of the literature was conducted for articles published during the period from 2 January 2003 to 21 October 2024. Articles published in English or Spanish were included. The keywords “Pentoxifylline” OR “BL 191” OR “trental” AND “cancer” were used for in vitro, in vivo, and clinical studies. PTX is an approved, accessible, and relatively safe drug. Furthermore there is a large body of experimental and clinical evidence of the beneficial effects of PTX in cancer therapy, either alone or in combination with antitumor drugs, sometimes even more effective than traditional chemotherapy regimens. However, it is necessary to carry out larger clinical trials in cancer patients to identify the benefits, adverse effects and even pharmacological interactions of PTX with current chemotherapy regimens and thus achieve a new drug repositioning that benefits our patients.

Introduction: Despite the improvement in survival in acute lymphoblastic leukemia (ALL), there are still cases with evasion of chemotherapy-induced apoptosis. The IKK/NF-κB signaling pathway contributes to antiapoptotic gene expression. Pentoxifylline (PTX) inhibits IkB phosphorylation, blocking NF-κB and antiapoptotic activity. Methods: We conducted a randomized, double-blind clinical trial on pediatric ALL patients undergoing induction therapy, assigning them to PTX or placebo group. Bone marrow aspirates were obtained on days 1, 8, 15, and 22. Apoptosis was assessed using Annexin-V/propidium iodide. Results: Results indicated that the PTX group exhibited higher apoptosis on day-8 (41.3% vs. 19.4%, p =0.029) and day-15 (35.0% vs. 14.2%, p p p =0.02). Patients achieving an MRD p =0.03); on day-15, patients with MRD p =0.03). The PTX group achieved an MRD of <0.01% earlier on days-8 and 15, along with a higher apoptosis rate, indicating a more favorable therapeutic response. In the entire cohort, patients achieving MRD <0.01% on day-8 or 15 displayed superior OS. Conclusion: Our study demonstrates that PTX enhances apoptosis and reduces MRD in pediatric acute lymphoblastic leukemia patients.Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02451774.

Liver cirrhosis is a pathology of varied etiology with a high prevalence and mortality, resulting in >1 million mortalities per year. Patients with liver cirrhosis typically have a survival time of 12 years following diagnosis. The treatment for this disease is directed at the complications of cirrhosis; however, to the best of our knowledge, the long‑term management of patients with cirrhosis has been scarcely studied. Pentoxifylline (PTX) is a non‑selective phosphodiesterase inhibitor with rheological activity and antioxidant, anti‑inflammatory and antifibrotic properties. PTX has been used in the treatment of peripheral arterial disease, inflammatory liver diseases and hepatocellular carcinoma with encouraging results. The aim of the present study was to evaluate the effect of PTX use on the survival of patients with compensated cirrhosis. For this purpose, a cross‑sectional study was performed at the Gastroenterology and Hepatitis C Department of Dr. Valentín Gómez Farias Hospital (Institute for Security and Social Services for State Workers, Zapopan, Mexico) from June, 1996 to December, 2019. The follow‑up time for these patients was 22.6 years (up to the end of the study period). In the present study, 326 patient files were analyzed and 118 patients with the disease were identified, 81 of whom (68.64%) died within 12 years after diagnosis. Of the included patients, 26 received PTX combined with PEG IFN‑α‑2a plus ribavirin, and 11 received PTX plus propranolol, with a median treatment duration of 20.6±0.8 years. Furthermore, 16 patients (43%) did not develop co‑morbidities within this time, and the transition to decompensated cirrhosis was 16.6 years, with a survival time of 20 years. Therefore, the results of the present study suggest that PTX may improve the long‑term survival of patients with compensated cirrhosis, rendering PTX a candidate for repurposing in the treatment of hepatic cirrhosis.

Prostate cancer (PCa) is a common and deadly disease in men. It is often diagnosed at advanced stages, at which point patients are treated mainly with docetaxel (DTX), which is effective but limited by resistance and side effects. Overactivation of the transcription factors NF-κB and STAT-3 plays a critical role in the development, progression, and chemoresistance of PCa. In this regard, the blockade of NF-κB with pentoxifylline (PTX) or STAT-3 with Stattic (STT) is known to increase the sensitivity of tumor cells to chemotherapy in both in vitro and in vivo models. We investigated whether simultaneous blockade with PTX and STT increases the efficacy of the DTX treatment in inducing apoptosis in metastatic castration-resistant PCa DU-145 cells. Our results showed that the combination of PTX + STT led to higher levels of apoptosis, regardless of whether or not DTX was present in the treatment. Determining caspases and ΔΨm indicates that the intrinsic caspase pathway of apoptosis is principally favored. In addition, this combination inhibited proliferation and colony formation and arrested the cell cycle in the G1 phase. These results indicate that the combination of the PTX + STAT-3 inhibitor could potentiate DTX effectively, opening the possibility of effective treatments in PCa.

Introduction and importance: Pyoderma gangrenosum is an unusual inflammatory pathology, with neutrophilic dermatosis, of unknown etiology. It is associated with diseases such as bowel disease. Generally, it is treated with anti-inflammatory drugs, corticosteroids, immunosuppressants, and antibodies against tumor necrosis factor, but relapse and adverse effects are persistent. Pentoxifylline is a drug with immunoregulatory and anti-inflammatory properties. Case presentation: A 47-year-old male with a diagnosis of ulcerative colitis initially managed favorably for 7 years with mesalazine. At 3 years of treatment, he presented a sudden ulcer that affected skin and subcutaneous tissue (13×10 cm) in the lower right limb. During the last 2 years, he was treated with mesalazine and infliximab with partial results and permanent relapses. Therefore, pentoxifylline was added to his treatment. Clinical discussion: The justification for the addition of pentoxifylline is mainly its action as an inhibitor of Nuclear Factor-kappa Beta (NF-κB) transcription, which stimulates the expression of proinflammatory interleukin genes such as IL-1, IL-6, IL- 8, and TNF-α and showing immunoregulatory and antioxidant activities. Conclusion: With pentoxifylline, this lesion healed at 6 weeks without relapses after 2 years.

To date, prostate cancer remains the most common tumor diagnosed in males and the second most common cause of cancer-related mortality. While current screening protocols can detect early disease, t... Tweetable abstract In prostate cancer, there remains a need for more accurate diagnostic, prognostic and treatment-response strategies utilizing less invasive sources. As such, miRNAs are promising...

Background/Aims. Prostate cancer (PCa) is one of the neoplasms with the highest incidence and mortality rate in men worldwide. Advanced stages of the disease are usually very aggressive, and most are treated with chemotherapeutic drugs that generally cause side effects in these patients. However, additional therapeutic targets such as the IL6R/STAT-3 axis and TIGIT have been proposed, mainly due to their relevance in the development of PCa and regulation of NK cell-mediated cytotoxicity. Here, we evaluate the effect of inhibitors directed against these therapeutic targets primarily via an analysis of NK cell function versus prostate cancer cells. Methods. We analyzed the secretion of cytokines, chemokines, and growth factors in 22Rv1, LNCaP, and DU145 cells. In these cells, we also evaluated the expression of NK ligands, IL6R, STAT-3, and phosporylated STAT-3. In NK-92 cells, we evaluated the effects of Stattic (Stt) and tocilizumab (Tcz) on NK receptors. In addition, we assessed if the disruption of the IL6R/STAT-3 pathway and blockade of TIGIT potentiated the cytotoxicity of NK-92 cells versus DU145 cells. Results. DU145 abundantly secretes M-CSF, VEGF, IL-6, CXCL8, and TGF-β. Furthermore, the expression of CD155 was found to increase in accordance with aggressiveness and metastatic status in the prostate cancer cells. Stt and Tcz induce a decrease in STAT-3 phosphorylation in the DU145 cells and, in turn, induce an increase of NKp46 and a decrease of TIGIT expression in NK-92 cells. Finally, the disruption of the IL6R/STAT-3 axis in prostate cancer cells and the blocking of TIGIT on NK-92 were observed to increase the cytotoxicity of NK-92 cells against DU145 cells through an increase in sFasL, granzyme A, granzyme B, and granulysin. Conclusions. Our results reveal that the combined use of inhibitors directed against the IL6R/STAT-3 axis and TIGIT enhances the functional activity of NK cells against castration-resistant prostate cancer cells.