Escape from immunotherapy: possible mechanisms that influence tumor regression/progression

Tumor escape is one major obstacle that has to be addressed prior to designing and delivering successful immunotherapy. There is compelling evidence to support the notion that immunogenic tumors, in murine models and cancer patients, can be rejected by the immune system under optimum conditions for activating adaptive and nonadaptive antitumor immune responses. Despite this capability, a large number of tumors continue to grow and evade recognition and/or destruction by the immune system. The limited success in current immunotherapeutic strategies may be due to a variety of reasons: failure of effector cells to compete with the growing tumor burden, production of humoral factors by tumors that locally block cytotoxicity, antigen/MHC loss, T-cell dysfunction, production of suppressor T cells—to name but a few causes for therapeutic ineffectiveness for the particular malignancy being treated. To optimize immunotherapy strategies, correction of immune-activating signals, eradication of inhibitory factors, and the evasion from newly developed immunoresistant tumor phenotypes need to be simultaneously considered

Immunotherapeutic potential of DISC-HSV and OX40L in cancer

Several vectors, viral and bacterial, have been developed over the past few years for means of generating an effective anti-tumor immune response. We have developed and studied a “model for immunotherapy” using a viral vector DISC-HSV, which efficiently transduces various tumor cell lines and offers a useful vehicle for the further development of cell based vaccines. The immunotherapeutic potential of DISC-HSV encoding GMCSF was demonstrated in a number of murine carcinoma models, leading to complete regression of well established tumors in up to 70% of the mice. Moreover, the therapeutic potential of DISC-HSV-GMCSF was significantly enhanced when used in combination therapy with either OX40L or dendritic cells (DC), even in poorly immunogenic tumor model. The ability of this vector to accept large gene inserts, its good safety profile, its ability to undergo only a single round of infection, the inherent viral immunostimulatory properties and its ability to infect various tumor cell lines efficiently, make DISC-HSV an ideal candidate vector for immunotherapy. The DISC- CT-26 tumor model has been used to investigate these mechanisms associated with immunotherapy – induced tumor rejection. Although CTL induction, was positively correlated with regression, MHC class I down regulation and accumulation of immature Gr1+ myeloid cells were shown to be the main immuno-suppressor mechanisms operating against regression and associated with progressive tumor growth

Meson Thermalization in Various Dimensions

In gauge/gravity duality framework the thermalization of mesons in strongly coupled (p+1)-dimensional gauge theories is studied for a general Dp-Dq system, q>=p, using the flavour Dq-brane as a probe. Thermalization corresponds to the horizon formation on the flavour Dq-brane. We calculate the thermalization time-scale due to a time-dependent change in the baryon number chemical potential, baryon injection in the field theory. We observe that for such a general system it has a universal behaviour depending only on the t'Hooft coupling constant and the two parameters which describe how we inject baryons into the system. We show that this universal behaviour is independent of the details of the theory whether it is conformal and/or supersymmetric.Comment: 26 pages, 2 figure

100 GHz Multiple Colliding Pulse Generation From Cleaved Facet-Free Multi-Section Semiconductor Laser Diode

We present a monolithically integrated mode-locked laser (MLL) with 25 GHz fundamental repetition rate frequency, which has been designed to operate in a fourth-order colliding regime, to generate 100 GHz. This device has been fabricated within a multi-project wafer (MPW) run in an InP-based active-passive generic foundry. The Fabry-Perot laser resonator, of around 1.66 mm length, is defined by two on-chip reflectors, eliminating the need of cleaved facet. Three saturable absorber sections are symmetrically located by spacing them a quarter of this total length, dividing the cavity into four gain segments. We show that this structure can generate an electrical beat note at 25 GHz as well as 100 GHz, with a linewidth of 350 kHz and 150 kHz, respectively, operating in passive operation regime

Spearhead Nanometric Field-Effect Transistor Sensors for Single-Cell Analysis.

Nanometric field-effect-transistor (FET) sensors are made on the tip of spear-shaped dual carbon nanoelectrodes derived from carbon deposition inside double-barrel nanopipettes. The easy fabrication route allows deposition of semiconductors or conducting polymers to comprise the transistor channel. A channel from electrodeposited poly pyrrole (PPy) exhibits high sensitivity toward pH changes. This property is exploited by immobilizing hexokinase on PPy nano-FETs to give rise to a selective ATP biosensor. Extracellular pH and ATP gradients are key biochemical constituents in the microenvironment of living cells; we monitor their real-time changes in relation to cancer cells and cardiomyocytes. The highly localized detection is possible because of the high aspect ratio and the spear-like design of the nano-FET probes. The accurately positioned nano-FET sensors can detect concentration gradients in three-dimensional space, identify biochemical properties of a single living cell, and after cell membrane penetration perform intracellular measurements

Prevalence and Correlates of Common Mental Disorders among Mothers of Young Children in Kilimanjaro Region of Tanzania.

Although poor maternal mental health is a major public health problem, with detrimental effects on the individual, her children and society, information on its correlates in low-income countries is sparse. This study investigates the prevalence of common mental disorders (CMD) among at-risk mothers, and explores its associations with sociodemographic factors. This population-based survey of mothers of children aged 0-36 months used the 14-item Shona Symptom Questionnaire (SSQ). Mothers whose response was "yes" to 8 or more items on the scale were defined as "at risk of CMD." Of the 1,922 mothers (15-48 years), 28.8% were at risk of CMD. Risk of CMD was associated with verbal abuse, physical abuse, a partner who did not help with the care of the child, being in a polygamous relationship, a partner with low levels of education, and a partner who smoked cigarettes. Cohabiting appeared to be protective. Taken together, our results indicate the significance of the quality of relations with one's partner in shaping maternal mental health. The high proportion of mothers who are at risk of CMD emphasizes the importance of developing evidence-based mental health programmes as part of the care package aimed at improving maternal well-being in Tanzania and other similar settings

The Effectiveness of Stingless Bees on Pollination of Bitter Melon Plants Momordica charantia L. (Cucurbitaceae)

This study aimed to measure the effectiveness of stingless bee Tetragonula cf. biroi pollination on the fruit formation of bitter melon Momordica charantia plants. We used hoods on the observed bitter melon plants. In the first hood, stingless bees are inserted to help pollinate 100 bitter melon plants, while in the other hoods, stingless bees are not inserted so that there is no assistance in pollinating the other 100 bitter melon plants. The method used is the focal sampling method for 25 days of observation. Based on the results of the study, stingless bee pollination assistance increased the percentage of the number of flowers that became fruit by 390%, the weight of seeds/fruit by 64%, number of seeds/fruit by 260%, fruit weight by 163%, fruit diameter by 91%, and fruit length by 86%. In addition to the size of the fruit, the shape of the bitter melon pollinated by bees is standard (long and straight). In contrast, the bitter melon that does not get pollination assistance grows with a bent shape resembling the letter "C." Bitter melon is an agricultural commodity that needs pollinating agents such as stingless bees because of its monoecy.

CDK7 inhibitors as anticancer drugs

Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494