Optimizing Outcomes in Mismatched Unrelated Donor Allogeneic Transplantation: Post-Transplant Cyclophosphamide's Dual Impact on Graft versus Host Disease Incidence and Overall Survival: Retrospective Analysis on Behalf of Polish Adult Leukemia Group.

Allogeneic hematopoietic cell transplantation (allo-HSCT) stands as an effective treatment method for various hematologic malignancies. However, graft-versus-host disease (GvHD), an intricate immunological phenomenon where donor immune cells target recipient tissues, remains a significant challenge, particularly in mismatched unrelated donors (MMUD). Post-transplant cyclophosphamide (PTCy) has emerged as a promising immunosuppressive strategy, revolutionizing haploidentical transplantation and demonstrating promise in MMUD settings. Background/Objectives: This study aimed to evaluate the impact of PTCy on MMUD allo-HSCT outcomes, specifically its effects on GvHD incidence and overall survival, compared to anthitymocyte globulin (ATG). Methods: One hundred seventy-four patients were classified into three groups based on the type of transplantation: PTCy-haplo (114/174; 65.5%), PTCy-MMUD (23/174; 13.2%), and ATG-MMUD (37/174; 21.2%). Results: Our findings showed that PTCy-MMUD significantly reduced acute GvHD occurrence compared to PTCy-haplo and ATG-MMUD approaches (p = 0.006). The delayed onset of acute GvHD in the PTCy-MMUD group suggests a more controlled immune reconstitution, contributing to the lower incidence. Importantly, PTCy-MMUD exhibited enhanced five-year overall survival rates, aligning with the notion that reduced GvHD correlates with improved patient outcomes (p = 0.032). Conclusions: We believe that this study contributes valuable insights into PTCy-MMUD's management, underscoring its potential to significantly reduce GvHD incidence and enhance survival outcomes. Although further investigations and clinical trials are warranted, this research underscores the promising role of PTCy-based GvHD prophylaxis in improving MMUD allo-HCT success.

The Benefits of the Post-Transplant Cyclophosphamide in Both Haploidentical and Mismatched Unrelated Donor Setting in Allogeneic Stem Cells Transplantation.

Allogeneic hematopoietic cell transplantation (alloHSCT) is a standard therapeutic approach for acute leukemias and many other hematologic malignancies. The proper choice of immunosuppressants applicable to different types of transplantations still requires strict and careful consideration, and data in this regard are divergent. For this reason, in this single-centered, retrospective study, we aimed to compare the outcome of 145 patients who received post-transplant cyclophosphamide (PTCy) for MMUD and haplo-HSCT or GvHD prophylaxis for MMUD-HSCT alone. We attempted to verify if PTCy is an optimal strategy in MMUD setting. Ninety-three recipients (93/145; 64.1%) underwent haplo-HSCT while 52 (52/145; 35.9%) underwent MMUD-HSCT. There were 110 patients who received PTCy (93 in haplo and 17 in MMUD group) and 35 patients received conventional GvHD prophylaxis based on antithymocyte globulin (ATG), cyclosporine (CsA), and methotrexate (Mtx) in the MMUD group only. Our study revealed that patients receiving post-transplant cyclophosphamide (PTCy) show decreased acute GvHD rates and CMV reactivation as well as a statistically lower number of CMV copies before and after antiviral treatment compared to the CsA + Mtx + ATG group. Taking into account chronic GvHD, the main predictors are donor age, ≥40 years, and haplo-HSCT administration. Furthermore, the survival rate of patients following MMUD-HSCT and receiving PTCy with tacrolimus and mycophenolate mofetil was more than eight times greater in comparison to patients receiving CsA + Mtx + ATG (OR = 8.31, p = 0.003). These data taken together suggest that the use of PTCy displays more benefits in terms of survival rate compared to ATG regardless of the type of transplantation performed. Nevertheless, more studies with a larger sample size are required to confirm the conflicting results in the literature studies.

Transcutaneous electrical acupoint stimulation to reduce opioid consumption in patients undergoing inguinal hernia repair: protocol for a randomized controlled trial.

BACKGROUND: The purpose of this study is to evaluate the efficacy and safety of transcutaneous electrical acupoint stimulation (TEAS) in the postoperative treatment of patients undergoing inguinal hernia repair compared with sham and no treatment group. METHODS: This study is a protocol for a three-armed, single-blinded, placebo-controlled randomized controlled trial. Ninety participants scheduled for inguinal hernia repair will be randomly assigned to the TEAS group (n = 30), sham group (n = 30), and control group (n = 30). The TEAS group will receive treatment using four portable coin-sized electro-stimulators at both local and distal acupuncture points. The sham group will receive sham treatment with mock electrostimulation. The treatment groups will receive mixed frequency stimulation (alternating at 2 and 100 Hz every 3 s) in continuous mode for 30 min at intervals of 2 h for 24 h postoperatively. The control group will receive postoperative pain control using patient-controlled analgesia (PCA) device. The primary outcome is the total morphine dose received in the postoperative period (mg) using PCA 24 h after surgery. The number of PCA demands (i.e., times the button will be pressed) and delivered bolus doses, score on the Visual Analogue Scale, opioid-related side effects, the requirement for supplemental medications, score on the Hospital Anxiety and Depression Scale (HADS), and blood levels of stress hormones cortisol and prolactin. DISCUSSION: The results of this trial will determine whether TEAS with intensified stimulation protocol is a safe and effective option for reducing analgesic consumption and postoperative pain. TRIAL REGISTRATION: ISRCTN76428396. Registered on 05 October 2020. https://www.isrctn.com/ISRCTN76428396.

Sociodemographic and Health-Related Factors Influencing Drug Intake among the Elderly Population.

Excessive drugs intake among the elderly population, including self-medication, constitutes an important public health problem. Polypharmacy may lead to numerous adverse health effects, which become more prevalent when combined with biological changes in seniors. In this cross-sectional study, 500 Polish adults aged ≥60 years (M = 67.9 ± 4.2) were asked to complete a questionnaire via telephone calls, allowing us to identify sociodemographic and health-related factors influencing the daily medications consumption. Our findings revealed that all of the participants were receiving medications; 60.2% of them receive at least 1 to 3 drugs per day (301/500). The most commonly used medications included antihypertensive drugs and analgesics (51.0% and 46.0%, respectively). Taking into account clinical conditions, independent predictors of receiving over 3 medications per day turned out to be (1) coronary artery disease (OR = 6.77; CI 95%, 2.86-16.1), (2) diabetes (OR = 3.23, CI 95%, 1.75-5.95), (3) asthma (OR = 4.87, CI 95%, 2.13-11.1), (4) heart failure (OR = 3.38, CI 95%, 1.59-7.19) and (5) gastroesophageal reflux disease (OR = 1.93, CI 95%, 1.03-3.62). Participants suffering from depression were more likely to take drugs for hypertension (OR = 1.70, CI 95%, 1.04-2.78), while those with anxiety and social loneliness took more painkillers (OR = 2.59, CI 95%, 1.58-4.26 and OR = 2.08, CI 95%, 1.38-3.13, respectively). The most significant sociodemographic factors increasing the drugs intake among the population included in our study were high body mass and subsequent increased BMI values (OR = 2.68, CI 95%, 1.50-4.77). Furthermore, living in a city with over 400,000 inhabitants increased the likelihood of taking antidepressants (OR = 2.18, CI 95%, 1.20-3.94). Our study revealed factors increasing the risk of excessive medications intake and hence, increased susceptibility to some iatrogenic diseases among the elderly population. These factors should be considered by primary care physicians while prescribing appropriate drugs to elderly patients.

BKV Related Hemorrhagic Cystitis-An Insight into Risk Factors and Later Complications-An Analysis on Behalf of Polish Adult Leukemia Group.

BK virus reactivation increases the likelihood of hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplant (HCT). In this study, we aimed to identify predictive and risk factors associated with the increased occurrence of this condition following HCT. On a group of 124 patients aged ≤71 years old (median 40 years) who underwent HCT, we analyzed sex, age, time from diagnosis to transplantation, type of conditioning, donor's relationship, age, and sex, the impact of immunosuppression with different drugs, and acute and chronic GVHD, BK viremia and viruria as potential factors increasing the risk of BK-related HC after HCT. HC occurred among 24 patients (24/124; 29.2%). A significant correlation was observed between HC incidences after HCT, BK viremia and viruria, and acute GVHD occurrence. Furthermore, the level of BKV DNA in serum at day +21 (>0.75 × 103) significantly impacted the patients' survival time. According to our results, the likelihood ratio of BKV-DNA on day +21 in serum is 6.25, indicating that this diagnostic test has the potential to be utilized in a clinical setting. These findings may be used as a voice in the discussion on implementing an optimal preemptive treatment in BKV reactivation after allogeneic HCT.

The Impact of Hypoglycemia on Patients with Diabetes Mellitus: A Cross-Sectional Analysis.

The increasing mortality and morbidity in patients with diabetes mellitus constitute a severe public health problem. The condition is recognized as a cause of impaired quality of life, high costs, and diminished productivity. In this study, we performed a cross-sectional analysis among 300 Polish participants with type 1 and type 2 diabetes to determine and classify risk factors associated with increased incidences of hypoglycemia. Including an open-access knowledge about the correlations between diabetes rates and human's lifestyle, we confirm that the frequency of smoking and drinking alcohol, low BMI, inappropriate diet, low physical activity, lack of vaccination against influenza and pneumococci, and co-existence of other comorbidities such as cardiovascular diseases, thyroid diseases, hyperlipidemia, retinopathy, and asthma elevate the risk of hypoglycemia. Furthermore, hypoglycemic patients were more often malnourished, depressed, irritated, and exposed to stress. In sum, the analysis of the interaction between diabetes and sociodemographic, environmental, or other disease-related risk factors provides strategies to optimize glycemic control and reduce the incidence of hypoglycemia. Furthermore, we believe our findings may constitute a basis for promoting health by adjusting available and implementing new preventive services reducing hypoglycemic episodes in diabetic patients.

How Sociodemographic Factors Impact the Utilization of Recommended Clinical Preventive Screening Services in Poland: A Nationwide Cross-Sectional Study.

Cardiovascular disease (CVD) and cancer are the most frequent causes of mortality in Poland. To date, no study in Poland has attempted to analyze the impact of sociodemographic factors on the utilization of all recommended preventive services for these diseases. To address this challenge, a nationwide cross-sectional study was conducted. One thousand adults aged 18 years or older were interviewed using computer-assisted telephone surveys conducted via random selection. A representative population was obtained in accordance with existing demographics per voivodeship in Poland. We assessed whether factors such as age, gender, body mass index (BMI), net income, household size, place of residence, and education impacted the odds ratio of utilizing recommended preventive services for CVD and cancer. We determined that elderly patients receive influenza vaccination, measure blood pressure, PSA concentration, glucose and lipid profiles, and undergo colonoscopy and mammography more often than younger counterparts. Men were more often influenza vaccinated (OR = 1.56, 95% CI: 1.07-2.27) than women, while women measured blood glucose more often than men (OR = 0.62, 95% CI: 0.42-0.93). Furthermore, net income < 2000 PLN, BMI < 24 kg/m2 and at least secondary education level were found to be crucial predictors of undergoing mammography (OR = 2.16; 95% CI: 1.26-3.72), cervical smear tests (OR = 1.99, 95% CI: 1.24-3.17), and lipid measurements (OR = 1.76, 95% CI: 1.07-2.91), respectively. Educating people and financial support seem to play a crucial role in implementing novel campaigns and preventive programs in Poland. Addressing each significant factor may be of paramount importance in improving the receipt of preventive services and warranting greater preventive care coverage in the Polish population.

Prevalence of Use of Preventive Services in Poland: Result from a Population-Based Nationwide Study.

Systematic reviews of scientific evidence have identified clinical services that prevent or ameliorate illness and reduce mortality. This study aimed to assess the prevalence of all recommended evidence-based preventive services in a publicly funded healthcare setting. We conducted a population-based nationwide cross-sectional computer-assisted telephone survey of 1000 Polish adults (response rate 42%). The self-reported use of all recommended clinical preventive services was assessed, including mammography, colonoscopy, blood glucose screening, vaccination, blood pressure screening, and preventive counselling. The results showed that only 6.4% of adults had received all recommended preventive screening, whereas only 4.3% had received appropriate counselling. General practitioner (GP) visits, blood pressure screening, blood glucose screening, and cervical smear were among the most commonly provisioned interventions, while flu vaccination, PSA assessment, and preventive counselling were among the least prevalent services. Despite the low uptake of preventive interventions, over 75% is interested in remote access to preventive services using telemedicine platforms and e-consultations. Our findings suggest that there are significant gaps in the receipt of preventive interventions. Further improvements require not only changes in the incentive system for healthcare providers, but also system-level innovation such as telemedicine solutions to deliver preventive services remotely and engage individuals in the monitoring process.

The Effect of a New Glucose-Methotrexate Conjugate on Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma Cell Lines.

Patients with hematologic malignancies require intensive therapies, including high-dose chemotherapy. Antimetabolite-methotrexate (MTX) has been used for many years in the treatment of leukemia and in lymphoma patients. However, the lack of MTX specificity causes a significant risk of morbidity, mortality, and severe side effects that impairs the quality of patients' life. Therefore, novel targeted therapies based on the malignant cells' common traits have become an essential treatment strategy. Glucose transporters have been found to be overexpressed in neoplastic cells, including hematologic malignancies. In this study, we biologically evaluated a novel glucose-methotrexate conjugate (Glu-MTX) in comparison to a free MTX. The research aimed to assess the effectiveness of Glu-MTX on chosen human lymphoma and leukemia cell lines. Cell cytotoxicity was verified by MTT viability test and flow cytometry. Moreover, the cell cycle and cellular uptake of Glu-MTX were evaluated. Our study reveals that conjugation of methotrexate with glucose significantly increases drug uptake and results in similar cytotoxicity of the synthesized compound. Although the finding has been confined to in vitro studies, our observations shed light on a potential therapeutic approach that increases the selectivity of chemotherapeutics and can improve leukemia and lymphoma patients' outcomes.

Phytochemicals in Gynecological Cancer Prevention.

Gynecological cancer confers an enormous burden among women worldwide. Accumulating evidence points to the role of phytochemicals in preventing cervical, endometrial, and ovarian cancer. Experimental studies emphasize the chemopreventive and therapeutic potential of plant-derived substances by inhibiting the early stages of carcinogenesis or improving the efficacy of traditional chemotherapeutic agents. Moreover, a number of epidemiological studies have investigated associations between a plant-based diet and cancer risk. This literature review summarizes the current knowledge on the phytochemicals with proven antitumor activity, emphasizing their effectiveness and mechanism of action in gynecological cancer.

In Vitro and In Vivo Efficacy of a Novel Glucose-Methotrexate Conjugate in Targeted Cancer Treatment.

Methotrexate (MTX) is a commonly used antimetabolite, which inhibits folate and DNA synthesis to be effective in the treatment of various malignancies. However, MTX therapy is hindered by the lack of target tumor selectivity. We have designed, synthesized and evaluated a novel glucose-methotrexate conjugate (GLU-MTX) both in vitro and in vivo, in which a cleavable linkage allows intracellular MTX release after selective uptake through glucose transporter-1 (GLUT1). GLU-MTX inhibited the growth of colorectal (DLD-1), breast (MCF-7) and lung (A427) adenocarcinomas, squamous cell carcinoma (SCC-25), osteosarcoma (MG63) cell lines, but not in WI-38 healthy fibroblasts. In tumor cells, GLU-MTX uptake increased 17-fold compared to unconjugated MTX. 4,6-O-ethylidene-α-D-glucose (EDG), a GLUT1 inhibitor, significantly interfered with GLU-MTX induced growth inhibition, suggesting a glucose-mediated drug uptake. Glu-MTX also caused significant tumor growth delay in vivo in breast cancer-bearing mice. These results show that our GLUT-MTX conjugate can be selectively uptake by a range of tumor cells to cause their significant growth inhibition in vitro, which was also confirmed in a breast cancer model in vivo. GLUT1 inhibitor EDG interfered with these effects verifying the selective drug uptake. Accordingly, GLU-MTX offers a considerable tumor selectivity and may offer cancer growth inhibition at reduced toxicity.

Overcoming Hypoxia-Induced Chemoresistance in Cancer Using a Novel Glycoconjugate of Methotrexate.

The oxygen and nutrient-deprived tumor microenvironment is considered a key mechanism responsible for cancer resistance to chemotherapy. Methotrexate (MTX) is a widely incorporated chemotherapeutic agent employed in the treatment of several malignancies. However, drug resistance and systemic toxicity limit the curative effect in most cases. The present work aimed to design, synthesize, and biologically evaluate a novel glucose-methotrexate conjugate (Glu-MTX). Our study showed that Glu-MTX exerts an increased cytotoxic effect on cancer cells in comparison to MTX in hypoxia (1% O2) and glucose starvation conditions. Furthermore, Glu-MTX was found to inhibit the proliferation and migration of cancer cells more effectively than MTX does. Our results demonstrate that the conjugation of MTX to glucose led to an increase in potency against malignant cells under oxygen and nutrient stress. The observations shed light on a potential therapeutic approach to overcome chemoresistance in cancer.

6-Shogaol enhances the anticancer effect of 5-fluorouracil, oxaliplatin, and irinotecan via increase of apoptosis and autophagy in colon cancer cells in hypoxic/aglycemic conditions.

BACKGROUND: The development and growth of colorectal cancer based on constitutive activation of numerous signaling pathways that stimulate proliferation and metastasis. Plant-derived agents excel by targeting multiple aspects of tumor progression. Previous investigations have shown that ginger derivatives- shogaols possess anti-cancer and anti-inflammatory effects. In the present study, we have examined the anti-cancer effects of 6-shogaol alongside with the most widely used chemotherapeutic agents/regimens in the tumor-like microenvironment conditions. METHODS: Cytotoxicity on two colon cancer cell lines (SW480 and SW620) was measured by MTT test. Apoptosisassay, immunocytochemical and Western blotting analysis for autophagy and apoptosis detection were performed. RESULTS: Here, we report that 6-shogaol by itself or in combination with chemotherapeutic agents/regimens exerted a cytotoxic effect on CRC cells. Cell death might be linked with the activation of autophagy and apoptosis-related pathways. In the tumor-like microenvironment, which is characterized by hypoxia and glucose starvation, 6-shogaol with chemotherapeutics is significantly more potent than conventional chemotherapy alone. CONCLUSIONS: Collectively, our data suggest that the addition of 6-shogaol to established chemotherapeutic regimens could potentially be a remarkable therapeutic strategy for colorectal cancer.

Glycoconjugation as a Promising Treatment Strategy for Psoriasis.

Despite the progress in the development of novel treatment modalities, a significant portion of patients with psoriasis remains undertreated relative to the severity of their disease. Recent evidence points to targeting the glucose transporter 1 and sugar metabolism as a novel therapeutic strategy for the treatment of psoriasis and other hyperproliferative skin diseases. In this review, we discuss glycoconjugation, an approach that facilitates the pharmacokinetics of cytotoxic molecules and ensures their preferential influx through glucose transporters. We propose pathways of glycoconjugate synthesis to increase effectiveness, cellular selectivity, and tolerability of widely used antipsoriatic drugs. The presented approach exploiting the heightened glucose requirement of proliferating keratinocytes bears the potential to revolutionize the management of psoriasis. SIGNIFICANCE STATEMENT: Recent findings concerning the fundamental role of enhanced glucose metabolism and glucose transporter 1 overexpression in the pathogenesis of psoriasis brought to light approaches that proved successful in cancer treatment. Substantial advances in the emerging field of glycoconjugation highlight the rationale for the development of glucose-conjugated antipsoriatic drugs to increase their effectiveness, cellular selectivity, and tolerability. The presented approach offers a novel therapeutic strategy for the treatment of psoriasis and other hyperproliferative skin diseases.

Osteopontin is differentially expressed in renal cell tumors.

Osteopontin (OPN) has been shown to play a significant role in regulating the aggressiveness of cancer cells and promote tumor growth. Evaluation of this phosphorylated extracellular glycoprotein expression may help estimate its use as a potential prognostic marker in tumorigenesis of different renal tumors. The objective of the present study was to characterize for the first time the expression pattern of OPN in primary renal tumors and correlate its association to tumor progression and survival. A total of 68 primary renal tumors (clear cell renal cell carcinoma, oncocytoma, renal cell carcinoma, invasive urothelial carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, papillary urothelial carcinoma) were analyzed by immunohistochemical staining and Western blot methods. Expression of OPN in relation to grading, histologic type of tumor, and survival was statistically assessed. Study data demonstrated that OPN is differentially expressed in various renal tumor cells types. It was shown that OPN is predominantly expressed at the protein level in clear cell renal cell carcinoma when compared to other types of renal tumors. In conclusion, osteopontin may be involved in the pathogenesis of renal tumors. However, the role of OPN expression in predicting the biological response requires further evaluation.

A comparative study of osteopontin expression, Ki67 index and prognosis in squamous cell carcinoma and cysts of the oral cavity.

BACKGROUND: Recent studies have shown a strong relationship between the expression of osteopontin and oral carcinogenesis. Osteopontin (OPN) has been shown to play a major role in regulating the aggressiveness of cancer cells and promote tumor growth. Odontogenic cysts are an essential aspect of oral and maxillofacial pathology. They are relatively frequent lesions with different clinical behavior. Some of them may have a proliferative pattern of growth and neoplastic nature. Evaluation of osteopontin expression with Ki-67 index may help examine clinical behavior and recurrence of oral squamous cell cancer and radicular cyst patients. METHODS: A total of 44 oral cavity cancer cases and 21 cysts samples were analyzed by immunohistochemical staining. Data used for analysis were derived from medical records. The following information was obtained from all patients' medical records: survival, age, sex, lymph node status, tumor size, and location, as well as grade and histologic type of tumor. Expression status of OPN and Ki-67 was statistically assessed. RESULTS: Our data demonstrated that for summary immunoreactive scores of OPN and Ki-67 expressions in OSCC vs. RC patients statistical significance was found for both markers' between OSCC and RC groups. Moreover, osteopontin is significantly higher expressed in larger OSCC tumors. CONCLUSIONS: In conclusion, the role of OPN expression both in oral squamous cancer cells and radicular cyst and possible correlation with demographic and clinicopathological features remain undetermined in some aspects, further high-powered studies to develop a more standardized assessment of Ki-67 and osteopontin expression in OSCC and are needed.

ARID1A/BAF250a is significantly overexpressed in primary invasive breast cancer.

BACKGROUND: ARID1A (also known as BAF250a, p270 or SMARCF1) is a major component of the mammalian SWI/SNF family that is involved in the regulation of the chromatin structure. ARID1A gene mutations have been associated with many types of malignancies, including breast cancer. This study aimed to explore the expression of BAF250a protein in breast cancer and its association with the clinical and pathological characteristics and prognosis of breast cancer. METHODS: We assessed the BAF250a expression in 119 invasive breast carcinomas samples and 92 healthy control and correlated this expression pattern with various clinical and pathologic parameters including histologic type and grade, tumor size, lymph node status, estrogen receptor (ER) status, progesterone receptor (PR) status. Immunohistochemical analysis of BAF250a, ER, PR, was carried out, and evaluation of stainings was performed. RESULTS: The mean value of BAF250a expression in the experimental group was higher than in healthy control (P=0.001). The expression is unrelated to age, menopausal status, lymph node status, tumor size and location, grade and histologic type of tumor, and hormonal status (ER, PR). CONCLUSIONS: These data suggest that BAF250a is overexpressed in breast cancers. BAF250a may play context-dependent tumor-promoting and tumor-suppressive roles in cancer.

Insulin enhancement of the antitumor activity of chemotherapeutic agents in colorectal cancer is linked with downregulating PIK3CA and GRB2.

The present state of cancer chemotherapy is unsatisfactory. New anticancer drugs that marginally improve the survival of patients continue to be developed at an unsustainably high cost. The study aimed to elucidate the effects of insulin (INS), an inexpensive drug with a convincing safety profile, on the susceptibility of colon cancer to chemotherapeutic agents: 5-fluorouracil (FU), oxaliplatin (OXA), irinotecan (IRI), cyclophosphamide (CPA) and docetaxel (DOC). To examine the effects of insulin on cell viability and apoptosis, we performed an in vitro analysis on colon cancer cell lines Caco-2 and SW480. To verify the results, we performed in vivo analysis on mice bearing MC38 colon tumors. To assess the underlying mechanism of the therapy, we examined the mRNA expression of pathways related to the signaling downstream of insulin receptors (INSR). Moreover, we performed Western blotting to confirm expression patterns derived from the genetic analysis. For the quantification of circulating tumor cells in the peripheral blood, we used the maintrac method. The results of our study show that insulin-pretreated colon cancer cells are significantly more susceptible to commonly used chemotherapeutics. The apoptosis ratio was also enhanced when INS was administered complementary to the examined drugs. The in vivo study showed that the combination of INS and FU resulted in significant inhibition of tumor growth and reduction of the number of circulating tumor cells. This combination caused a significant downregulation of the key signaling substrates downstream of INSR. The results indicate that the downregulation of PIK3CA (phosphatidylinositol 3-kinase catalytic subunit alpha), which plays a critical role in cell signaling and GRB2 (growth factor receptor-bound protein 2), a regulator of cell proliferation and differentiation may be responsible for the sensitizing effect of INS. These findings were confirmed at protein levels by Western blotting. In conclusion, these results suggest that INS might be potentially applied to clinical use to enhance the therapeutic effectiveness of chemotherapeutic drugs. The findings may become a platform for the future development of new and inexpensive strategies for the clinical chemotherapy of tumors.

Clinical validation of nuclear factor kappa B expression in invasive breast cancer.

Breast cancer is the most commonly diagnosed cancer in Polish women. The expression of transcription nuclear factor kappa B, a key inducer of inflammatory response promoting carcinogenesis and cancer progression in breast cancer, is not well-established. We assessed the nuclear factor kappa B expression in a total of 119 invasive breast carcinomas and 25 healthy control samples and correlated this expression pattern with several clinical and pathologic parameters including histologic type and grade, tumor size, lymph node status, estrogen receptor status, and progesterone receptor status. The data used for the analysis were derived from medical records. An immunohistochemical analysis of nuclear factor kappa B, estrogen receptor, and progesterone receptor was carried out and evaluation of stainings was performed. The expression of nuclear factor kappa B was significantly higher than that in the corresponding healthy control samples. No statistical difference was demonstrated in nuclear factor kappa B expression in relation to age, menopausal status, lymph node status, tumor size and location, grade and histologic type of tumor, and hormonal status (estrogen receptor and progesterone receptor). Nuclear factor kappa B is significantly overexpressed in invasive breast cancer tissues. Although nuclear factor kappa B status does not correlate with clinicopathological findings, it might provide important additional information on prognosis and become a promising object for targeted therapy.

Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide.

The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.