BACKGROUND: Patients with autoimmune conditions receiving immunosuppressants are at risk of non-Hodgkin lymphomas (NHL). Vedolizumab (anti-α4β7-integrin antibody), a treatment-of-choice for Crohn\'s disease (CD), reduces inflammatory lymphocyte trafficking into the intestinal mucosa. This effect is believed to be confined to the colon.
METHODS: We report the case of a CD patient on vedolizumab for five years who developed pediatric-type follicular lymphoma. Work-up prior to therapy revealed a reduction in circulating T-lymphocytes and their suppressed response to mitogens. Rituximab, cyclophosphamide, vincristine, and prednisone chemo-immunotherapy resulted in durable lymphoma remission, and vedolizumab treatment was continued. While the patient\'s T-lymphocyte population and immunoglobulin production recovered, the T-lymphocyte mitogen response remained suppressed.
CONCLUSIONS: This patient\'s NHL may be linked to receiving anti-α4β7 therapy. Further research could be beneficial to determine if proactive surveillance for NHL and other systemic diseases is indicated in patients on vedolizumab.

Mechanical forces are critical for regulating many biological processes such as cell differentiation, proliferation, and death. Probing the continuously changing molecular force through integrin receptors provides insights into the molecular mechanism of rigidity sensing in cells; however, the force information is still limited. Here, we built a coil-shaped DNA origami (DNA nanospring, NS) as a force sensor that reports the dynamic motion of single integrins as well as the magnitude and orientation of the force through integrins in living cells. We monitored the extension with nanometer accuracy and the orientation of the NS linked with a single integrin by the shape of the fluorescence spots. We used acoustic force spectroscopy to estimate the force-extension curve of the NS and determined the force with an ∼10% force error at a broad detectable range from subpicoNewtons (pN) to ∼50 pN. We found single integrins tethered with the NS moved several tens of nanometers, and the contraction and relaxation speeds were load dependent at less than ∼20 pN but robust over ∼20 pN. Fluctuations of the traction force orientation were suppressed with increasing load. Our assay system is a potentially powerful tool for studying mechanosensing at the molecular level.

Glioblastoma (GBM) is the most common malignant brain tumor. Less than 1% of patients survive longer than 10 years. A 77-year-old woman was diagnosed with MGMT-methylated GBM in 2009. The patient received cilengitide as part of the CENTRIC clinical trial in conjunction with standard radiation and chemotherapy. Though the study was halted in 2013, our patient received cilengitide until 2016 with no radiographic evidence of recurrence thus far. This is the oldest reported GBM patient with greater than 10-year survival. Her exceptional response may have been influenced by MGMT promoter methylation status and PTEN expression.

Integrin receptors are established drug targets, but many of the drugs that have been developed act as partial agonists, inducing the receptor into a high-affinity, ligand-binding state. Lin et al. discovered a general mechanism to circumvent this problem-stabilizing a key water molecule that prevents receptor activation. Their findings are likely to impact future therapeutic development.

Started as an academic curiosity more than two decades ago, the idea that ion channels can regulate cellular processes in ways that do not depend on their conducting properties (non-ionic functions) gained traction and is now a flourishing area of research. Channels can regulate physiological processes including actin cytoskeletal remodeling, cell motility, excitation-contraction coupling, non-associative learning and embryogenesis, just to mention some, through non-ionic functions. When defective, non-ionic functions can give rise to channelopathies involved in cancer, neurodegenerative disease and brain trauma. Ion channels exert their non-ionic functions through a variety of mechanisms that range from physical coupling with other proteins, to possessing enzymatic activity, to assembling with signaling molecules. In this article, we take stock of the field and review recent findings. The concept that emerges, is that one of the most common ways through which channels acquire non-ionic attributes, is by assembling with integrins. These integrin-channel complexes exhibit broad genotypic and phenotypic heterogeneity and reveal a pleiotropic nature, as they appear to be capable of influencing both physiological and pathological processes.

The cellular functions are regulated by a complex interplay of diffuse and local signals. Studying the latter is challenging, but experimental work in cell physiology has led to recognize that understanding a cell\'s dynamics requires a deep comprehension of local fluctuations of cytosolic regulators. Macromolecular complexes are major determinants of local signaling. Multienzyme assemblies limit the diffusion restriction to reaction kinetics by direct exchange of metabolites. Likewise, close coupling of ion channels and transporters modulates the ion concentration around a channel mouth or transporter binding site. Extreme signal locality is brought about by conformational coupling between membrane proteins, as is typical of mechanotransduction. A paradigmatic case is integrin-mediated cell adhesion. Sensing the extracellular microenvironment and providing an appropriate response are essential in growth and development and have innumerable pathological implications. The process involves bidirectional signal transduction by complex supramolecular structures that link integrin receptors to ion channels and transporters, growth factor receptors, cytoskeletal elements, and other regulatory elements. The dynamics of such complexes are only beginning to be understood. A thoroughly studied example is the association between integrin receptors and the voltage-gated K+ channels Kv11.1. These channels are widely expressed in early embryos, where their physiological roles are poorly understood and apparently different from the shaping of action potential firing in the adult. Hints about these roles come from studies in cancer cells, where Kv11.1 is often overexpressed and appears to reassume functions it presumably exerts during embryogenesis, such as controlling cell proliferation/differentiation, apoptosis, and migration. Kv11.1 is implicated in these processes through its linking to integrin subunits, which in turn regulates channel expression. Specific cellular functions, such as proliferation and migration, appear to be modulated by distinct conformational states of the channel (e.g., open and closed), whose balance is affected by the link with integrin subunits.

General population is exposed to dibutyl phthalate (DBP) through continuous use of various consumer products. DBP exhibits its effects mainly on the endocrine and reproductive system but it can also affect the function of the vasculature; however, the underlying mechanisms behind DBP-induced vascular dysfunction are not fully understood. To infer pathways, molecular functions, biological processes, and human diseases associated with DBP exposure, we integrated the toxicogenomic data obtained from the 4-week-long exposure of human vascular endothelial cells (ECs) to three environmentally relevant concentrations of DBP with the in silico analysis. Nine genes were affected by DBP exposure: six of the integrin family, VCAM1, ICAM1, and MMP2. As shown by the in silico analysis, changes in DBP-affected genes could affect extracellular matrix and binding of molecules and cells to ECs, thereby altering cell adhesion and migration. Several pathways, molecular functions, and biological processes were further identified to provide insight into the DBP-vascular disease relationships and the potential mechanism of action. The top three human disease categories associated with DBP exposure and vascular dysfunction include cardiovascular, cerebrovascular, and immune system diseases. Integration of experimental and in silico approaches may offer better understanding of the potential human health risks associated with DBP exposure.

Cancer is a major health problem worldwide and the second leading cause of death following cardiovascular diseases. Breast cancer is the leading cause of mortality and morbidity among women and one of the most common malignant neoplasms prompt to metastatic disease. In the present review, the mechanisms of the major cell adhesion molecules involved in tumor invasion are discussed, focusing on the case of breast cancer. A non-systematic updated revision of the literature was performed in order to assemble information regarding the expression of the adhesion cell molecules associated with metastasis.

BACKGROUND: α4β7 is a gut-homing integrin heterodimer that can act as a non-essential binding molecule for HIV. A previous study in heterosexual African women found that individuals with higher proportions of α4β7 expressing CD4+ T cells were more likely to become infected with HIV, as well as present with faster disease progression. It is unknown if this phenomenon is also observed in men who have sex with men (MSM) or people who inject drugs (PWID).
METHODS: MSM and transgender women who seroconverted as part of the HVTN 505 HIV vaccine trial and PWID who seroconverted during the ALIVE cohort study were selected as cases and matched to HIV-uninfected controls from the same studies (1:1 and 1:3, respectively). Pre-seroconversion PBMC samples from cases and controls in both studies were examined by flow cytometry to measure levels of α4β7 expression on CD4+ T cells. Multivariable conditional logistic regression was used to compare α4β7 expression levels between cases and controls. A Kaplan-Meier curve was used to examine the association of α4β7 expression pre-seroconversion with HIV disease progression.
RESULTS: In MSM and transgender women (n = 103 cases, 103 controls), there was no statistically significant difference in the levels of α4β7 expression on CD4+ T cells between cases and controls (adjusted odds ratio [adjOR] =1.10, 95% confidence interval [CI]=0.94,1.29; p = 0.246). Interestingly, in PWID (n = 49 cases, 143 controls), cases had significantly lower levels of α4β7 expression compared to their matched controls (adjOR = 0.80, 95% CI = 0.68, 0.93; p = 0.004). Among HIV-positive PWID (n = 47), there was no significant association in HIV disease progression in individuals above or below the median level of α4β7 expression (log-rank p = 0.84).
CONCLUSIONS: In contrast to findings in heterosexual women, higher α4β7 expression does not predict HIV acquisition or disease progression in PWID or MSM.
BACKGROUND: This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. The study was also supported by extramural grants from NIAID T32AI102623 (E.U.P.), and UM1AI069470.

Cancer is a disease characterized by its high morbidity and mortality, mainly due to its metastatic ability. Metastasis is a multi-step process beginning with detachment of tumor cells from the primary tumor and leading ultimately to the establishment of a new tumoral site. This cascade includes intravascular migration of tumor cells either individually or collectively and the expansion of cancer cells at metastatic sites that is dependent on certain conditions such as an immunosuppressive environment. In this paper, blockers of tumor cell migration and suppressors of immunotolerance at metastatic sites are reviewed as an illustration of early and later phases intervention, respectively. A combination of these two therapeutics will be advocated based on the proposition of correlation between the pattern of tumor cell migration and the mechanism of immunotolerance induction. By extension, the \'\'delayed complementarity\'\' will be introduced as an approach to formulate new anticancer drug combinations.