Cross-selective Deoxygenative Coupling of Aliphatic Alcohols: Installation of Methyl Groups including Isotopic Labels by Nickel Catalysis.

Nickel-catalyzed cross-electrophile coupling reactions of two aliphatic alcohol derivatives remain a challenge. Herein, we report a nickel-catalyzed reductive methylation reaction of aliphatic mesylates with methyl tosylate. This reaction provides straightforward access to compounds bearing aliphatic methyl groups from alkyl alcohol derivatives. Isotopically labelled substrates and reagents can be employed in the reaction to provide perdeuterated and 13C-labelled products. This transformation can be achieved by employing stoichiometric Mn reductant or electrochemically. Additionally, mechanistic experiments show that alkyl iodides are key intermediates in the transformation which undergo a stereoablative reaction via radical intermediates.

Halogenation Reactions of Alkyl Alcohols Employing Methyl Grignard Reagents.

Grignard reagents are commonly used as carbanion equivalents. Herein, we report an example of Grignard reagents acting as halide nucleophiles to form alkyl iodides and bromides. We establish that Grignard reagents can convert alkyl mesylates into alkyl halides, as well as be employed in a one-pot halogenation reaction starting from alcohols, which proceed through mesylate intermediates. The halogenation reaction is confirmed to occur by an SN2 pathway with inversion of configuration and is demonstrated to be efficient on multi-gram scale.

Interleukin-2 enhances CD4+ T cell memory by promoting the generation of IL-7R alpha-expressing cells.

The common gamma chain cytokines interleukin (IL)-2 and IL-7 are important regulators of T cell homeostasis. Although IL-2 is implicated in the acute phase of the T cell response, IL-7 is important for memory T cell survival. We asked whether regulated responsiveness to these growth factors is determined by temporal expression of the cytokine-specific IL-2 receptor (R) alpha and IL-7Ralpha chains. We demonstrate that IL-2Ralpha is expressed early after priming in T cell receptor-transgenic CD4(+) T cells, whereas IL-7Ralpha expression is lost. In the later stage of the response, IL-7Ralpha is reexpressed while IL-2Ralpha expression is silenced. This reciprocal pattern of IL-2Ralpha/IL-7Ralpha expression is disturbed when CD4(+) T cells are primed in the absence of IL-2 signals. Primed IL-2(-/-) or CD25(-/-) (IL-2Ralpha(-/-)) CD4(+) T cells, despite showing normal induction of activation markers and cell division, fail to reexpress IL-7Ralpha late in the response. Because the generation of CD4(+) memory T cells is dependent on IL-7-IL-7Ralpha interactions, primed IL-2(-/-) or CD25(-/-) CD4(+) T cells develop poorly into long-lived memory cells. Retrovirus-mediated expression of IL-7Ralpha in IL-2(-/-) T cells restores their capacity for long-term survival. These results identify IL-2 as a factor regulating IL-7Ralpha expression and, consequently, memory T cell homeostasis in vivo.

Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function.

An immature intestinal epithelial barrier may predispose infants and children to many intestinal inflammatory diseases, such as infectious enteritis, inflammatory bowel disease, and necrotizing enterocolitis. Understanding the factors that regulate gut barrier maturation may yield insight into strategies to prevent these intestinal diseases. The claudin family of tight junction proteins plays an important role in regulating epithelial paracellular permeability. Previous reports demonstrate that rodent intestinal barrier function matures during the first 3 weeks of life. We show that murine paracellular permeability markedly decreases during postnatal maturation, with the most significant change occurring between 2 and 3 weeks. Here we report for the first time that commensal bacterial colonization induces intestinal barrier function maturation by promoting claudin 3 expression. Neonatal mice raised on antibiotics or lacking the toll-like receptor adaptor protein MyD88 exhibit impaired barrier function and decreased claudin 3 expression. Furthermore, enteral administration of either live or heat-killed preparations of the probiotic Lactobacillus rhamnosus GG accelerates intestinal barrier maturation and induces claudin 3 expression. However, live Lactobacillus rhamnosus GG increases mortality. Taken together, these results support a vital role for intestinal flora in the maturation of intestinal barrier function. Probiotics may prevent intestinal inflammatory diseases by regulating intestinal tight junction protein expression and barrier function. The use of heat-killed probiotics may provide therapeutic benefit while minimizing adverse effects.

A Nickel-Catalyzed Cross-Electrophile Coupling Reaction of 1,3-Dimesylates for Alkylcyclopropane Synthesis: Investigation of Stereochemical Outcomes and Radical Lifetimes.

Understanding mechanistic details of the nickel-catalyzed coupling reactions of Csp3 alcohol derivatives is key to developing selective reactions of this widely prevalent functional group. In this manuscript, we utilize a combination of experimental data and DFT studies to define the key intermediates, stereochemical outcome, and competing pathways of a nickel-catalyzed cross-electrophile coupling reaction of 1,3-dimesylates. Stereospecific formation of a 1,3-diiodide intermediate is achieved in situ by the Grignard reagent. The overall stereoablative stereochemical outcome is due to a nickel-catalyzed halogen atom abstraction with a radical rebound that is slower than epimerization of the alkyl radical. Finally, lifetimes of this alkyl radical intermediate are compared to radical clocks to enhance the understanding of the lifetime of the secondary alkyl radical.

Stereospecific Nickel-Catalyzed Cross-Electrophile Coupling Reaction of Alkyl Mesylates and Allylic Difluorides to Access Enantioenriched Vinyl Fluoride-Substituted Cyclopropanes.

Cross-electrophile coupling reactions involving direct C-O bond activation of unactivated alkyl sulfonates or C-F bond activation of allylic gem-difluorides remain challenging. Herein, we report a nickel-catalyzed cross-electrophile coupling reaction between alkyl mesylates and allylic gem-difluorides to synthesize enantioenriched vinyl fluoride-substituted cyclopropane products. These complex products are interesting building blocks with applications in medicinal chemistry. Density functional theory (DFT) calculations demonstrate that there are two competing pathways for this reaction, both of which initiate by coordination of the electron-deficient olefin to the low-valent nickel catalyst. Subsequently, the reaction can proceed by oxidative addition of the C-F bond of the allylic gem-difluoride moiety or by directed polar oxidative addition of the alkyl mesylate C-O bond.

Commensal Escherichia coli reduces epithelial apoptosis through IFN-alphaA-mediated induction of guanylate binding protein-1 in human and murine models of developing intestine.

Appropriate microbial colonization protects the developing intestine by promoting epithelial barrier function and fostering mucosal tolerance to luminal bacteria. Commensal flora mediate their protective effects through TLR9-dependent activation of cytokines, such as type I IFNs (alpha, beta) and IL-10. Although IFN-beta promotes apoptosis, IFN-alpha activates specific antiapoptotic target genes whose actions preserve epithelial barrier integrity. We have recently identified guanylate binding protein-1 (GBP-1) as an antiapoptotic protein, regulated by both type I and type II IFNs, that promotes intestinal epithelial barrier integrity in mature intestine. However, the mechanisms by which commensal bacteria regulate epithelial apoptosis during colonization of immature intestine and the contributions of GBP-1 are unknown. The healthy newborn intestine is initially colonized with bacterial species present in the maternal gastrointestinal tract, including nonpathogenic Escherichia coli. Therefore, we examined the influence of commensal E. coli on cytokine expression and candidate mediators of apoptosis in preweaned mice. Specifically, enteral exposure of 2 wk-old mice to commensal E. coli for 24 h selectively increased both IFN-alphaA and GBP-1 mRNA expression and prevented staurosporine-induced epithelial apoptosis. Exogenous IFN-alphaA treatment also induced GBP-1 expression and protected against staurosporine-induced apoptosis in a GBP-1 dependent manner, both in vitro and ex vivo. These findings identify a role for IFN-alphaA-mediated GBP-1 expression in the prevention of intestinal epithelial apoptosis by commensal bacteria. Thus IFN-alphaA mediates the beneficial effects of commensal bacteria and may be a promising therapeutic target to promote barrier integrity and prevent the inappropriate inflammatory responses seen in developing intestine as in necrotizing enterocolitis.

Tibio-pedal arterial pressure assessment during endovascular intervention to improve quality-of-life in patients with intermittent claudication.

Objective: The aim of this study is to compare the quality-of-life (QOL) outcomes and the tibio-pedal arterial pressure post-endovascular intervention. Background: Physiological assessment of peripheral arterial lesions is infrequently performed during endovascular interventions. Materials and methods: We retrospectively reviewed all 343 patients with intermittent claudication who underwent an endovascular intervention via tibio-pedal artery access from October 2018 to May 2021. The baseline and post-intervention tibio-pedal arterial pressures from the pedal sheaths were measured. QOL was assessed using a pre-validated Walking Impairment Questionnaire (WIQ) score before and at 30-day after intervention. We compared the baseline tibio-pedal arterial pressure, post-intervention tibio-pedal arterial pressure, delta pressure (post-intervention minus baseline), baseline WIQ scores, 30-day WIQ scores, and delta score (30-day minus baseline). Results: All 343 patients had successful tibio-pedal accesses. The average tibio-pedal arterial pressure at baseline was 87.0 ± 1.8 mmHg vs. 135.5 ± 1.7 mmHg post-intervention (p < 0.001). Average baseline and 30-day WIQ scores were summation (99.8 ± 3.3 vs. 115.0 ± 3.1, p < 0.001), walking distance (35.7 ± 1.3 vs. 42.5 ± 1.3, p < 0.001), walking speed (21.1 ± 0.9 vs. 23.6 ± 0.8, p = 0.036), stair climbing (4.7 ± 1.4 vs. 24.2 ± 1.4, p = 0.019), and symptoms (18.8 ± 0.2 vs. 20.1 ± 0.2, p < 0.001), respectively. When comparing the increased post-intervention tibio-pedal arterial pressure <60 mmHg vs. ≥60 mmHg, the average delta WIQ scores were all significantly improved with summation (10.0 ± 3.9 to 25.8 ± 5.5, p = 0.01), walking distance (4.1 ± 1.7 to 9.8 ± 2.5, p = 0.02), walking speed (1.5 ± 1.1 to 4.3 ± 1.5, p = 0.02), stair climbing (2.3 ± 1.8 to 9.4 ± 2.5, p = 0.02), and symptoms (1.0 ± 0.3 to 1.8 ± 0.4, p = 0.04), respectively. Conclusion: Increasing the post-intervention tibio-pedal arterial pressure by 60 mmHg can enhance QOL as suggested by improvement of WIQ scores.

The Use of Bumper Wire Technique and Intravascular Ultrasound for Precise Aorto-Ostial Stenting.

Background: Aorto-ostial interventions are challenging due to the limitations of contemporary equipment, imprecise ostial demarcation, and problematic ostial lesion characteristics. Suboptimal stent placement is common and portends worse clinical outcomes. Procedural and long-term outcomes of the bumper wire technique with intravascular ultrasound (IVUS) assessment have not been investigated. Methods: A single-center retrospective study was conducted. Patients who underwent ostial lesion percutaneous coronary intervention (PCI) with the bumper wire technique between January 2019 and September 2020 were identified. The primary endpoint was to determine the geographic miss rate defined by inadequate ostial coverage or excess stent protrusion of > 2 mm by IVUS or angiography. The secondary endpoint was target lesion failure (TLF) at 6 months after PCI, defined as the composite of cardiovascular death, target vessel myocardial infarction (MI), and target lesion revascularization. Results: In total, 45 patients were identified. The average age was 71.7 years old, and 85.4% were men. Indication for PCI was acute coronary syndrome in about a third of patients. Twenty-six patients had left main ostial lesions and 19 patients had right coronary artery ostial lesions. Geographic miss was detected in two patients (4.4%): one patient (2.2%) had excess proximal stent protrusion and one patient (2.2%) had an ostial miss. Six patients were lost to follow-up. TLF, stroke, or major bleeding were not observed in any of the patients. Conclusion: The bumper wire technique is safe and efficient with low rates of geographic miss or adverse clinical outcomes. This is the first study to confirm precise aorto-ostial stent implantation with the bumper wire technique using IVUS confirmation.

The probiotic Lactobacillus GG may augment intestinal host defense by regulating apoptosis and promoting cytoprotective responses in the developing murine gut.

Necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality in preterm infants. Although its pathogenesis is poorly understood, inappropriate apoptosis of the mucosal epithelia has been implicated. Recent clinical trials have shown that probiotics may reduce the incidence of NEC, and probiotics have been shown to suppress intestinal epithelial apoptosis in cultured cells. However, little is known about their mechanism of action in the developing intestine in vivo. Here, we confirm that the probiotic Lactobacillus rhamnosus GG (LGG) reduces chemically induced intestinal epithelial apoptosis in vitro. Furthermore, we report for the first time that LGG administered orally to live animals can reduce chemically induced epithelial apoptosis ex vivo, as measured by staining for active caspase 3 and terminal deoxynucleotidyltransferase. Using cDNA microarray analysis from the intestine of live, orally inoculated mice, we show that LGG up-regulates a battery of genes with known and likely cytoprotective effects. These studies indicate that probiotics such as LGG may augment intestinal host defenses in the developing intestine by stimulating antiapoptotic and cytoprotective responses. Because apoptosis may be a precursor to NEC, understanding the mechanism behind probiotic modulation of apoptotic pathways may allow for development of more specifically targeted therapies or preventive strategies in the future.

Necrotizing enterocolitis: recent scientific advances in pathophysiology and prevention.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants in the neonatal intensive care unit. Here we review the epidemiology and pathophysiology of NEC, with an emphasis on the latest research findings and potential areas for future research. NEC continues to be one of the most devastating and unpredictable diseases affecting premature infants. Despite decades of research, the pathogenesis of this disease remains unclear, and prevention and treatment strategies are limited. Hopefully, future studies aimed at understanding premature intestinal defenses, commensal or probiotic bacterial influences, and possible genetic predisposition will lead to the improvement of prevention and treatment strategies.

Necrotising enterocolitis.

Necrotising enterocolitis is one of the most common gastrointestinal emergencies in newborn infants. Here we review the epidemiology, clinical presentation, and pathophysiology of the disease, as well as strategies for diagnosis, management, and prevention. Necrotising enterocolitis is one of the most devastating and unpredictable diseases affecting premature infants. Despite decades of research, its pathogenesis remains unclear; diagnosis can be difficult; and treatment is challenging. We will need to improve our understanding of intestinal defences in premature infants, dietary and bacterial factors, and genetic effects that could predispose infants to necrotising enterocolitis before we can develop new strategies for prevention and treatment.

Childhood linear IgA bullous disease triggered by amoxicillin-clavulanic acid.

Linear immunoglobulin A bullous disease is an autoimmune subepidermal blistering disease that has been described in both children and adults. Reports have shown that as many as two-thirds of occurrences may be drug-induced. The offending drugs include antibiotics, predominantly vancomycin, nonsteroidal anti-inflammatory agents and diuretics. We report childhood linear immunoglobulin A bullous dermatosis developing following amoxicillin-clavulanic acid administration. The patient presented with characteristic blisters in an annular fashion, likened to a ''crown of jewels.'' The diagnosis was confirmed by the presence of a linear band of immunoglobulin A at the dermoepidermal junction on direct immunofluorescence. The lesions resolved with withdrawal of the drug, and systemic therapy was not required. We review the current literature and concepts of drug-induced linear immunoglobulin A bullous disease.

HLA alleles and risk of cervical intraepithelial neoplasia among southwestern American Indian women.

An increase in cervical intraepithelial neoplasia (CIN) has been described in American Indian women in New Mexico. Differences in human leukocyte antigen (HLA) alleles have been reported in cervical intraepithelial neoplasia (CIN) compared with controls in other populations. We investigated HLA alleles and CIN in Southwest American Indian women. The case control study included 89 women with biopsy-proven CIN II/III (diagnosed November 1994 through October 1997) and 271 similar women with normal cervical epithelium from the same clinics. DRB1, DQB1, and DPB1 alleles were determined using DNA typing techniques. DQA1 and HLA-A allele typing was included for some subjects (randomly chosen n = 37 and n = 163 cases and controls, respectively). We found a decreased risk of CIN with DRB1*1402 (OR 0.5, 95% CI 0.3-0.9) and an increased risk with DRB1*1501 (OR 2.7, 95% CI 0.9-7.3). Additionally, DQA1*0102 was associated with increased risk (OR 4.5, 95% CI 1.3-5.3) and HLA-A*02 with decreased risk (OR 0.4, CI 0.2-0.9). Our findings are discussed along with studies in other populations.

Identifying Depressed Patients With a High Risk of Comorbid Anxiety in Primary Care.

BACKGROUND: Depressive and anxiety disorders are highly prevalent in the primary care setting. There is evidence that patients with depression and comorbid anxiety are more severely impaired than patients with depression alone and require aggressive mental health treatment. The goal of this study was to assess the impact of comorbid anxiety in a primary care population of depressed patients. METHOD: 342 subjects diagnosed with a DSM-IV-defined major depressive episode, dysthymia, or both were asked 2 questions about the presence of comorbid anxiety symptoms (history of panic attacks and/or flashbacks). Patient groups included depression only (N = 119), depression and panic attacks (N = 51), depression and flashbacks (N = 97), and depression and both panic attacks and flashbacks (N = 75). Groups were compared on demographics, mental health histories, and health-related quality-of-life variables. Data were gathered from January 1998 to March 1999. RESULTS: Those patients with depression, panic attacks, and flashback symptoms as compared with those with depression alone were more likely to be younger, unmarried, and female. The group with depression, panic attacks, and flashbacks was also more likely to have more depressive symptoms, more impaired health status, worse disability, and a more complicated and persistent history of mental illness. Regression analysis revealed that the greatest impact on disability, presence of depressive symptoms, and mental health outcomes was associated with panic attacks. CONCLUSION: By asking 2 questions about comorbid anxiety symptoms, primary care providers evaluating depressed patients may be able to identify a group of significantly impaired patients at high risk of anxiety disorders who might benefit from collaboration with or referral to a mental health specialist.

Comparison of 3 Depression Screening Methods and Provider Referral in a Veterans Affairs Primary Care Clinic.

BACKGROUND: Concern about underdiagnosis and undertreatment of depression in primary care has led to support for routine screening. Although multiple screening instruments exist, we are not aware of studies to date that have compared different screening strategies, e.g., how the instrument is administered: by whom and in what setting. This study compared 3 separate screening strategies in terms of patient flow, coverage, patient characteristics, and other factors with the usual care system of provider referral. METHOD: We analyzed existing data from a completed randomized team trial of collaborative care depression treatment in which patients who met DSM-IV criteria for current major depressive disorder, dysthymic disorder, or both were recruited using the usual care system of provider referral (provider) and 3 separate screening strategies: (1) a 2-stage waiting room screening interview (waiting), (2) an in-clinic screen consisting of 2 self-report items embedded in a larger survey (in-clinic), and (3) a 2-stage self-report mail survey (mail). The team trial and analysis were conducted between January 1998 and July 2003. RESULTS: The usual care system of provider referral identified the most depressed patients and had relatively good coverage compared with the 3 screening strategies. Of the 3 screening strategies, the in-clinic strategy had the best coverage, while the mail strategy had the worst coverage. Provider referral patients were younger and had fewer chronic medical illnesses than did other patients. The waiting strategy identified more patients with bipolar affective disorder. CONCLUSION: While different strategies may be optimal for different resource levels and patient characteristics, this study suggests that an in-clinic self-report survey may be the best adjunct to provider referral for efficiently increasing coverage. This study also suggests that different screening strategies may capture different patient populations.

Addressing substance abuse and violence in substance use disorder treatment and batterer intervention programs.

BACKGROUND: Substance use disorders and perpetration of intimate partner violence (IPV) are interrelated, major public health problems. METHODS: We surveyed directors of a sample of substance use disorder treatment programs (SUDPs; N=241) and batterer intervention programs (BIPs; N=235) in California (70% response rate) to examine the extent to which SUDPs address IPV, and BIPs address substance abuse. RESULTS: Generally, SUDPs were not addressing co-occurring IPV perpetration in a formal and comprehensive way. Few had a policy requiring assessment of potential clients, or monitoring of admitted clients, for violence perpetration; almost one-quarter did not admit potential clients who had perpetrated IPV, and only 20% had a component or track to address violence. About one-third suspended or terminated clients engaging in violence. The most common barriers to SUDPs providing IPV services were that violence prevention was not part of the program's mission, staff lacked training in violence, and the lack of reimbursement mechanisms for such services. In contrast, BIPs tended to address substance abuse in a more formal and comprehensive way; e.g., one-half had a policy requiring potential clients to be assessed, two-thirds required monitoring of substance abuse among admitted clients, and almost one-half had a component or track to address substance abuse. SUDPs had clients with fewer resources (marriage, employment, income, housing), and more severe problems (both alcohol and drug use disorders, dual substance use and other mental health disorders, HIV + status). We found little evidence that services are centralized for individuals with both substance abuse and violence problems, even though most SUDP and BIP directors agreed that help for both problems should be obtained simultaneously in separate programs. CONCLUSIONS: SUDPs may have difficulty addressing violence because they have a clientele with relatively few resources and more complex psychological and medical needs. However, policy change can modify barriers to treatment integration and service linkage, such as reimbursement restrictions and lack of staff training.

Developmental biology of gut-probiotic interaction.

While our current knowledge of probiotic interaction in the developing gut remains poorly understood, emerging science is providing greater biological insight into their mechanism of action and therapeutic potential for human disease. Given their beneficial effects, probiotics remain promising agents in neonatal gastrointestinal disorders. Probiotics may restore or supply essential bacterial strains needed for gut maturation and homeostasis, particularly in hosts where this process has been disrupted. Here we highlight the unique characteristics of developing intestinal epithelia with a focus on gut development and colonization as well as the inflammatory propensity of immature epithelia. Additionally, we review potential mechanisms of beneficial probiotic interaction with immature intestinal epithelia including immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis and maintenance of barrier function. Improved knowledge of gut-probiotic interaction in developing epithelia will allow for a better understanding of how probiotics exert their beneficial effects and help guide their therapeutic use.

FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence.

Oncogenic activation of the RAS-ERK MAP kinase signaling pathway can lead to uncontrolled proliferation but can also result in apoptosis or premature cellular senescence, both regarded as natural protective barriers to cell immortalization and transformation. In FGFR3-related skeletal dyplasias, oncogenic mutations in the FGFR3 receptor tyrosine kinase cause profound inhibition of cartilage growth resulting in severe dwarfism, although many of the precise mechanisms of FGFR3 action remain unclear. Mutated FGFR3 induces constitutive activation of the ERK pathway in chondrocytes and, remarkably, can also cause both increased proliferation and apoptosis in growing cartilage, depending on the gestational age. Here, we demonstrate that FGFR3 signaling is also capable of inducing premature senescence in chondrocytes, manifested as reversible, ERK-dependent growth arrest accompanied by alteration of cellular shape, loss of the extracellular matrix, upregulation of senescence markers (alpha-GLUCOSIDASE, FIBRONECTIN, CAVEOLIN 1, LAMIN A, SM22alpha and TIMP 1), and induction of senescence-associated beta-GALACTOSIDASE activity. Our data support a model whereby FGFR3 signaling inhibits cartilage growth via exploiting cellular responses originally designed to eliminate cells harboring activated oncogenes.

Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells.

Pancreatic cancer is an aggressive malignancy that is generally refractory to chemotherapy, thus posing experimental and clinical challenges. In this study, the antiproliferative effect of the triterpenoid compound cucurbitacin B was tested in vitro and in vivo against human pancreatic cancer cells. Dose-response studies showed that the drug inhibited 50% growth of seven pancreatic cancer cell lines at 10(-7) mol/L, whereas clonogenic growth was significantly inhibited at 5 x 10(-8) mol/L. Cucurbitacin B caused dose- and time-dependent G(2)-M-phase arrest and apoptosis of pancreatic cancer cells. This was associated with inhibition of activated JAK2, STAT3, and STAT5, increased level of p21(WAF1) even in cells with nonfunctional p53, and decrease of expression of cyclin A, cyclin B1, and Bcl-XL with subsequent activation of the caspase cascade. Interestingly, the combination of cucurbitacin B and gemcitabine synergistically potentiated the antiproliferative effects of gemcitabine on pancreatic cancer cells. Moreover, cucurbitacin B decreased the volume of pancreatic tumor xenografts in athymic nude mice by 69.2% (P < 0.01) compared with controls without noticeable drug toxicities. In vivo activation of JAK2/STAT3 was inhibited and expression of Bcl-XL was decreased, whereas caspase-3 and caspase-9 were up-regulated in tumors of drug-treated mice. In conclusion, we showed for the first time that cucurbitacin B has profound in vitro and in vivo antiproliferative effects against human pancreatic cancer cells, and the compound may potentate the antiproliferative effect of the chemotherapeutic agent gemcitabine. Further clinical studies are necessary to confirm our findings in patients with pancreatic cancer.