The role of myeloid cells in modulating the therapeutic effectiveness of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal cancer, accounting for 3.2% of new cancer cases yearly but nearly 8% of all yearly cancer mortalities. Over the past twenty years, our understanding of cancer biology has greatly improved which has resulted in vastly improved prognoses for many cancers. However, the prognosis of pancreatic ductal adenocarcinoma has not improved despite the advance in cancer treatments. This is especially apparent with cancer immunotherapies, a newer therapeutic strategy that utilizes the innate defense mechanism of the body to target malignancies. Immune checkpoint inhibitors are a type of cancer immunotherapy that act by inhibiting the PD-1/PD-L1 and CTLA-4 immune checkpoint pathways and allowing T lymphocytes to proliferate and generate an antitumor response. They have greatly improved the prognosis for many types of malignancies, but clinical studies show that immune checkpoint inhibition has had a limited effect on the prognosis of PDAC. Recent studies have demonstrated that the immune microenvironment of PDAC is highly immunosuppressive, which is a probable factor in limiting the therapeutic efficacy of immune checkpoint inhibitors. Myeloid derived suppressor cells (MDSCs) are a main component of the immune microenvironment in PDAC. They are immature cells of myeloid origin that express CD11b+Gr-1+ on their surface, making them phenotypically distinct from mature dendritic cells. Their infiltration of the PDAC microenvironment early on in the course of the disease is promoted in a large part by the cytokine GM-CSF. MDSCs are believed to contribute to the limited efficacy of immune checkpoint inhibitor therapy both directly and indirectly. Indirect mechanisms are mediated by promoting the activity of other immunosuppressive cells in the PDAC microenvironment such as tumor associated macrophages and regulatory T lymphocytes. MDSCs induce the transformation of naïve CD4+ T lymphocytes into protumorigenic regulatory T lymphocytes. They also promote the polarization of macrophages to the tumor associated macrophage phenotype (IL-10high IL-12low) by secreting IL-10, which decreases IL-12 synthesis by macrophages present in the tumor microenvironment. On top of mediating immunosuppression through other cell types, MDSCs directly mediate immunosuppression by decreasing the amounts of amino acids necessary for anti-tumor immunity in the tumor microenvironment and disrupting the activity of antigen presenting cells and the signaling needed to initiate a cytotoxic T lymphocyte response. The decreased amount of arginine limits the ability of T cells to proliferate, resulting in a weaker cytotoxic response. These mechanisms limit the antitumor response against pancreatic ductal adenocarcinoma, resulting in the decreased response to immune checkpoint inhibitor therapy observed in clinical trials. Future attempts to strengthen the anti-tumor immune response must be combinatorial therapies that incorporate therapeutic strategies that seek to alleviate MDSC-mediated immunosuppression of T lymphocytes from the tumor microenvironment in addition to the more widely available immune checkpoint inhibitor therapy. Such therapeutics are currently being studied in murine models and have shown promising preliminary results but have yet to have been examined in clinical trials. These therapies are an ideal avenue to explore in a search for more effective therapy for this highly lethal disease

QoS Constrained Optimal Sink and Relay Placement in Planned Wireless Sensor Networks

We are given a set of sensors at given locations, a set of potential locations for placing base stations (BSs, or sinks), and another set of potential locations for placing wireless relay nodes. There is a cost for placing a BS and a cost for placing a relay. The problem we consider is to select a set of BS locations, a set of relay locations, and an association of sensor nodes with the selected BS locations, so that number of hops in the path from each sensor to its BS is bounded by hmax, and among all such feasible networks, the cost of the selected network is the minimum. The hop count bound suffices to ensure a certain probability of the data being delivered to the BS within a given maximum delay under a light traffic model. We observe that the problem is NP-Hard, and is hard to even approximate within a constant factor. For this problem, we propose a polynomial time approximation algorithm (SmartSelect) based on a relay placement algorithm proposed in our earlier work, along with a modification of the greedy algorithm for weighted set cover. We have analyzed the worst case approximation guarantee for this algorithm. We have also proposed a polynomial time heuristic to improve upon the solution provided by SmartSelect. Our numerical results demonstrate that the algorithms provide good quality solutions using very little computation time in various randomly generated network scenarios

Will women’s choice of position in first stage of labor affect labor process?

Background: Controlling the process of childbirth has disabled the parturient to embrace the most spontaneous position of delivery but constricting her to assume a recumbent position. Objective of this study was to study if alternating comfortable maternal positioning i.e., recumbent and alternative position have any influence in the process of labor, type of delivery, neonatal well-being.Methods: Study conducted an observation study on term pregnant women. Study inclusion criteria included all term pregnant women. Exclusion criteria included multiple pregnancies, preterm patient, severe pre-eclampsia, and eclampsia, preterm premature rupture of membranes, sever intrauterine growth restricted fetus. The measured date were maternal general characteristics, duration of labor process, type of delivery and neonatal outcome. Patients were divided into two groups. Group A - if they spent more than 50% in a recumbent position and Group B - any other alternating position.Results: A total 250 women were equally included in this study. The demographic characteristics were matched in both groups and found no significant difference. In the process of labor, Group B had a difference of 1 hours as compared to Group A and the rate of cervical dilation was also faster in Group B. Both of these variables were found to be statistically significant. However, there were no significant difference in the terms of type of delivery and neonatal outcome.Conclusions: The ancient practice of recumbent position during labor is to be discarded as alternating maternal position during the process of labor may a positive influence on the total duration labor. However even though it may or may not have an influence on the other outcome such as route of delivery and neonatal outcome, it is best to encourage women to move and deliver in the most comfortable position

Impromptu Deployment of Wireless Relay Networks: Experiences Along a Forest Trail

We are motivated by the problem of impromptu or as- you-go deployment of wireless sensor networks. As an application example, a person, starting from a sink node, walks along a forest trail, makes link quality measurements (with the previously placed nodes) at equally spaced locations, and deploys relays at some of these locations, so as to connect a sensor placed at some a priori unknown point on the trail with the sink node. In this paper, we report our experimental experiences with some as-you-go deployment algorithms. Two algorithms are based on Markov decision process (MDP) formulations; these require a radio propagation model. We also study purely measurement based strategies: one heuristic that is motivated by our MDP formulations, one asymptotically optimal learning algorithm, and one inspired by a popular heuristic. We extract a statistical model of the propagation along a forest trail from raw measurement data, implement the algorithms experimentally in the forest, and compare them. The results provide useful insights regarding the choice of the deployment algorithm and its parameters, and also demonstrate the necessity of a proper theoretical formulation.Comment: 7 pages, accepted in IEEE MASS 201

Maternal sepsis- an audit in a tertiary care center in South India

Background: Objective of this study was to audit the cases of maternal sepsis and analyze their maternal and fetal outcomes.Methods: A retrospective analysis of cases of maternal sepsis was undertaken for one year. Cases were taken as infection with fever, tachycardia, tachypnea, low oxygen saturation, high or low white blood counts and clinical or laboratory evidence of organ dysfunction and were analyzed. Demographic profile, gestational age at the time of diagnosis, organisms & their sources of infection was noted. Maternal outcomes of abortion, preterm delivery, need for intensive care unit (ICU) / high dependency unit (HDU) stay, blood and blood products, surgical interventions for the control of infection, culture-positive rate, source of organism, antibiotic usage and maternal mortality were analyzed. Fetal outcomes of early fetal demise, preterm birth, intrauterine death, stillbirth and term birth were studied.  Results: There were a total of 2327 deliveries, with 2333 live births during the study period. Twenty-two cases were diagnosed with sepsis, of which 17 survived, and five died. The incidence of maternal sepsis was 9.4/1000 live births & maternal deaths were 22.7%. Ninety percent were in the age group of 21-39 years, 68% were referred, 59% were post-delivery. Fifty nine percent of women who survived, and none of the women who died had medical co-morbidities. Respiratory tract followed by genitourinary tract were the most common source of infection, though culture was negative in 54.5% of the cases. The organisms grown were varied, with Escherichia coli (3/10) contributing to 30% of the culture positive cases. Spontaneous abortion and preterm delivery were 18% each, 36% required surgical intervention, 81% required ICU and 64.7% HDU stay. Seventy-seven had live birth.Conclusions: Maternal sepsis is an evolving preventable health burden. Early recognition requires a high index of clinical suspicion, even in the absence of risk factors. Mortality to morbidity ratio is very high in maternal sepsis. The timing of sepsis determines the fetal outcomes

Respostas ecofisiológicas e morfológicas do pau-rosa (Aniba rosaeodora Ducke) aos diferentes níveis de sombreamento, em condição de viveiro.

Publicado também em: Boletim da Faculdade de Ciências Agrárias do Pará, Belém, PA, n. 30, p. 119-132, jul./dez. 1998

Povezanost genskih varijanti akvaporina 7 s kvalitetom sjemena u murrah bivola

The Aquaporin 7 (AQP7) gene, a member of the aqua-glyceroporins, was characterised using Polymerase Chain Reaction-Single Strand Conformation Polymorphism (PCR-SSCP) analysis, in order to investigate the association of genetic variants of the AQP7 gene with semen quality in Murrah bulls. In this study, genomic DNA was extracted from the blood of Murrah bulls (n = 69) using the high salt method. Sequence data were analyzed using Bio Edit software (version 7.0.5) for detecting single nucleotide polymorphisms (SNPs). Statistical analysis was carried out using repeated GLM procedure measures (SAS 9.3). Analysis revealed 17 different SSCP variants in the AQP7 gene in Murrah buffaloes. Three unique SSCP band patterns were observed in exons 1 and 4. Exons 5, 7 and 8 showed five, four and two unique SSCP band patterns, respectively. Sequence analysis revealed a total of 20 SNPs (8 in exonic and 12 in intronic region). PCR-SSCP variants of exon 5 were significantly associated (P<0.01) with sperm concentration. SSCP variants of exons 5 and 8 were associated (P<0.05) with sperm viability and post thaw motility (PTM), respectively. The study revealed a high degree of genetic variability in the AQP7 gene in Murrah bulls. The SSCP variants observed are associated with semen parameters which suggests the possibility of using the AQP7 gene as a candidate gene for identification of markers for semen quality traits in buffaloes.Gen akvaporin 7 (AQP7), koji pripada akvagliceroporinima, analiziran je kombinacijom lančane reakcije polimerazom i utvrđivanjem polimorfizma jednolančane konformacije (PCR-SSCP) s ciljem da se istraži povezanost genskih varijanti s kvalitetom sjemena u Murrah bivola. Genomska DNA izdvojena je iz krvi bivola (n = 69) high salt metodom. Za otkrivanje polimorfizma pojedinačnih nukleotida (SNP) sekvencije su analizirane programom Bio Edit (verzija 7.0.5). Statistička analiza provedena je GLM procedurom ponovljenih mjerenja (SAS 9.3). Analiza je pokazala 17 različitih SSCP varijanti AQP7gena u Murrah bivola. Tri jedinstvena SSCP rasporeda linija utvrđena su u egzonima 1 i 4. Egzoni 5, 7 i 8 pokazali su pet, četiri i dva jedinstvena SSCP rasporeda linija. Sekvenciranje je pokazalo ukupno 20 SNP-a (8 u egzonima i 12 u intronima). PCR-SSCP varijante egzona 5 statistički su značajno povezane (P<0,01) s koncentracijom sjemena. SSCP varijante egzona 5 i 8 značajno su povezane (P<0,05) s vijabilnošću spermija i njihovom pokretljivošću nakon odmrzavanja. Istraživanje je pokazalo visok stupanj genetičke varijabilnosti akvaporina 7 u Murrah bivola. Utvrđene SSCP varijante koje su povezane s pokazateljima kakvoće sjemena upućuju na mogućnost upotrebe akvaporina 7 gena kao kandidatnog gena za identifikaciju biljega kvalitete sjemena bivola

Assessment of genetic diversity among Malnad Gidda, Punganur and Vechur-dwarf cattle breeds of India using microsatellite markers

The genetic diversity among 3 dwarf breeds of cattle in India, viz. Malnad Gidda, Punganur and Vechur were analysed using 12 sets of microsatellite markers. All 11 amplified microsatellite loci were polymorphic with a mean number of alleles of 7.818±1.66 across breeds and in different breeds it ranged from 7.273 in Malnad Gidda to 3.546 in Vechur. The mean polymorphic information content (PIC) value observed and expected heterozygosity values across the population were 0.642, 0.610 and 0.683, respectively. A moderate level of inbreeding was observed with the inbreeding estimates ranging from -0.027 (ILSTS6) to 0.271 (HAUT24). Among the 3 breeds the highest mean number of alleles (7.273), mean PIC value (0.639), observed heterozygosity (0.630) and lower inbreeding estimates at majority of loci were observed in Malnad Gidda cattle indicating high degree of heterozygosity compared to Punganur and Vechur breeds. Even though departure from Hardy Weinberg Equilibrium (HWE) was found in Vechur and Punganur cattle population at majority of the loci, the population combining the 3 breeds was maintained at HWE with respect to most of loci under study. The genetic distance analysis revealed highest genetic distance between Vechur and Punganur (0.331) and lowest between Malnad Gidda and Punganur (0.125)