Final outcomes analysis of the cell product SQZ-PBMC-HPV Phase 1 trial in incurable HPV16+ solid tumors shows improved overall survival in patients with increased CD8+ T cell tumor infiltration.

Cancer vaccines strive to induce robust, antigen-targeted, T-cell-mediated immune responses but have struggled to produce meaningful regression in solid tumors. An autologous cell vaccine, SQZ-PBMC-HPV, was developed by SQZ Biotechnologies using microfluidic squeezing technology to load PBMCs with HPV16 E6 and E7 antigens in HLA-A*02+ patients. The SQZ-PBMC-HPV-101 Phase 1 trial (NCT04084951) enrolled patients with incurable HPV16+ cancers. Here, we present a post hoc analysis of the relationship between Posttreatment CD8+ T cell infiltration and patient outcomes. SQZ-PBMC-HPV was administered as monotherapy every 3 weeks. Tumor samples were collected pre-dose and post-dose 4 weeks after treatment start. Biomarkers including CD8, MHC-I, E6, E7, GZMB, and Ki67 were evaluated by immunohistochemistry, immunofluorescence, and RNA in situ hybridization, and were correlated with clinical response, survival, and drug product composition. Eighteen patients had paired pre- and post-dose biopsies. Six (33%) had an increase in CD8+ T cell density in tumor parenchyma between screening and C2D8. Patients with increased CD8+ T cell density had improved disease control rate (66.7% vs 16.7%) and median overall survival (606.5 days vs 170.0 days, p = 0.0078). Drug product was significantly enriched for higher T cells and lower monocytes in the increased CD8+ T cell density group. In patients with incurable HPV16+ solid tumors treated with SQZ-PBMC-HPV, an increase in CD8+ T cell density within the tumor parenchyma was associated with superior disease control rate and overall survival. The product composition for patients with increased CD8+ T cell density was enriched for T cells.

Exposure of Akwesasne Mohawk women to polychlorinated biphenyls and hexachlorobenzene is associated with increased serum levels of thyroid peroxidase autoantibodies.

Persistent organic pollutants (POPs) including polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), and dichlorodiphenyltrichloroethane (p,p'-DDT) were reported to influence immunological activity. As endocrine-disrupting chemicals (EDC), these pollutants may disrupt normal thyroid function and act as catalysts for development of autoimmune thyroid disease by directly and indirectly affecting levels of thyroid peroxidase antibodies (TPOAbs). Native American communities are disproportionately exposed to harmful toxicants and are at an increased risk of developing an autoimmune disease. The aim of this study was to determine the association between POPs and TPOAbs in serum obtained from Native American women. This assessment was used to measure whether increased risk of autoimmune thyroid disease occurred as a result of exposure to POPs. Data were collected from 183 Akwesasne Mohawk women, 21-38 years of age, between 2009 and 2013. Multivariate analyses were conducted to determine the association between toxicant exposure and levels of TPOAbs. In multiple logistic regression analyses, exposure to PCB congener 33 was related to elevated risk of individuals possessing above normal levels of TPOAbs. Further, HCB was associated with more than 2-fold higher risk of possessing above normal levels of TPOAbs compared to women with normal levels of TPOAbs. p,p'-DDE was not associated with TPOAb levels within this study. Exposure to PCB congener 33 and HCB was correlated with above normal levels of TPOAbs, a marker of autoimmune thyroid disease. Additional investigations are needed to establish the causes and factors surrounding autoimmune thyroid disease which are multiple and complex.

Phase 1 study to determine the safety and dosing of autologous PBMCs modified to present HPV16 antigens (SQZ-PBMC-HPV) in HLA-A*02+ patients with HPV16+ solid tumors.

We conducted a dose escalation Phase 1 study of autologous PBMCs loaded by microfluidic squeezing (Cell Squeeze® technology) with HPV16 E6 and E7 antigens (SQZ-PBMC-HPV), in HLA-A*02+ patients with advanced/metastatic HPV16+ cancers. Preclinical studies in murine models had shown such cells resulted in stimulation and proliferation of antigen specific CD8+ cells, and demonstrated antitumor activity. Administration of SQZ-PBMC-HPV was every 3 weeks. Enrollment followed a modified 3+3 design with primary objectives to define safety, tolerability, and the recommended Phase 2 dose. Secondary and exploratory objectives were antitumor activity, manufacturing feasibility, and pharmacodynamic evaluation of immune responses. Eighteen patients were enrolled at doses ranging from 0.5 × 106 to 5.0 × 106 live cells/kg. Manufacture proved feasible and required < 24 h within the overall vein-to-vein time of 1 - 2 weeks; at the highest dose, a median of 4 doses were administered. No DLTs were observed. Most related TEAEs were Grade 1 - 2, and one Grade 2 cytokine release syndrome SAE was reported. Tumor biopsies in three patients showed 2 to 8-fold increases in CD8+ tissue infiltrating lymphocytes, including a case that exhibited increased MHC-I+ and PD-L1+ cell densities and reduced numbers of HPV+ cells. Clinical benefit was documented for the latter case. SQZ-PBMC-HPV was well tolerated; 5.0 × 106 live cells/kg with double priming was chosen as the recommended Phase 2 dose. Multiple participants exhibited pharmacodynamic changes consistent with immune responses supporting the proposed mechanism of action for SQZ-PBMC-HPV, including patients previously refractory to checkpoint inhibitors.

Educational Case: HER-2 Positive Breast Cancer.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Ripretinib intrapatient dose escalation after disease progression provides clinically meaningful outcomes in advanced gastrointestinal stromal tumour.

PURPOSE: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and platelet-derived growth factor receptor α kinase signalling. Ripretinib showed preliminary efficacy in patients with advanced gastrointestinal stromal tumour (GIST) in a phase I study across a range of doses. Results were confirmed in the phase III INVICTUS study, and ripretinib 150 mg once daily (QD) was subsequently approved as a ≥fourth-line therapy. Here, we report the phase I study results of intrapatient dose escalation (IPDE) in patients with GIST treated across second, third and later lines of therapy. METHODS: Patients with advanced GIST who experienced disease progression (PD) at ripretinib 150 mg QD could dose escalate to 150 mg twice daily (BID). Progression-free survival (PFS) 1 was calculated from the date of the first dose of ripretinib 150 mg QD to PD (as per Response Evaluation Criteria in Solid Tumours 1.1); PFS2 was from the date of IPDE (150 mg BID) to PD or death. Treatment-emergent adverse events (TEAEs) were summarised by dosing periods and compared descriptively. RESULTS: Of 142 patients with GIST receiving ripretinib 150 mg QD, 67 underwent IPDE. IPDE provided benefit across all lines of therapy; the median PFS2 was 5.6, 3.3 and 4.6 months for patients on second-, third- and ≥fourth-line therapy, respectively. A partial metabolic response after IPDE was demonstrated in 13 of 37 patients with available positron emission tomography scans. TEAEs reported at both doses were similar. CONCLUSION: Ripretinib IPDE after PD provided continued clinical benefit in advanced GIST across second, third and later lines of therapy with a similar safety profile to that observed with the QD regimen.

NMR Quantification of Hydrogen-Bond-Accepting Ability for Organic Molecules.

The hydrogen-bond-accepting abilities for more than 100 organic molecules are quantified using 19F and 31P NMR spectroscopy with pentafluorobenzoic acid (PFBA) and phenylphosphinic acid (PPA) as commercially available, inexpensive probes. Analysis of pyridines and anilines with a variety of electronic modifications demonstrates that changes in NMR shifts can predict the secondary effects that contribute to H-bond-accepting ability, establishing the ability of PFBA and PPA binding to predict electronic trends. The H-bond-accepting abilities of various metal-chelating ligands and organocatalysts are also quantified. The measured Δδ(31P) and Δδp(19F) values correlate strongly with Hammett parameters, pKa of the protonated HBA, and proton-transfer basicity (pKBH+).

NMR quantification of H-bond donating ability for bioactive functional groups and isosteres.

The H-bond donating ability for 127 compounds including drug fragments and isosteres have been quantified using a simple and rapid method with 31P NMR spectroscopy. Functional groups important to medicinal chemistry were evaluated including carboxylic acids, alcohols, phenols, thioic acids and nitrogen group H-bond donors. 31P NMR shifts for binding to a phosphine oxide probe have a higher correlation with equilibrium constants for H-bonding (log KHA) than acidity (pKa), indicating that these binding experiments are representative of H-bonding ability and not proton transfer. Additionally, 31P NMR binding data for carboxylic acid isosteres correlates with physicochemical properties such as lipophilicity, membrane permeability and plasma protein binding. This method has been used to evaluate the H-bond donating ability of small molecule drug compounds such as NSAIDs and antimicrobials.

Hired helpers at the nest: The association between life-cycle servants and net fertility in North Orkney, 1851-1911.

OBJECTIVES: The presence of kin is often, but not always, associated with higher fertility in historical populations. However, the effect of other household members on fertility is less frequently studied. While not genetically related, life-cycle servants lived and worked alongside household members and may have provided assistance to reproducing families. Female servants in particular may have helped mothers with small children through direct help with childcare activities or by replacing the economic effort of mothers whose work was not compatible with childcare. This study examines the presence of servants in the households of married women of reproductive age to assess whether households with young children are more likely to also have servants. MATERIALS AND METHODS: This study uses individual-level census data from North Orkney, Scotland (1851-1911) to investigate the relationship between the presence of servants in households and a measure of recent net marital fertility, the number of women's own-children under age 5, using logistic regression models. RESULTS: Households with young children were more likely to have a female, but not male, servant in the household after controlling for the effects of other possible helpers, including older children, mothers, and mothers-in-law. DISCUSSION: These findings are consistent with prior research that indicates the importance of female labor to smallholder agricultural households and suggests that female servants may have provided support to reproducing families. Life-cycle servants should be considered one component of biocultural reproduction in historical Northwest Europe. The use of hired help is not restricted to contemporary or elite groups.

NMR Quantification of the Effects of Ligands and Counterions on Lewis Acid Catalysis.

The relative Lewis acidity of a variety of metal-ligand catalyst complexes is quantified using 31P NMR spectroscopy. Three 31P NMR probes, including two new bidentate binding probes, are compared on the basis of different binding modes (i.e., monodentate vs bidentate) and the relative scale of their downfield shift upon binding to Lewis acid complexes. Bidentate coordination of catalyst complexes including metal catalysts, ligands, and counterions were assessed due to their importance to asymmetric catalysis. The effect of ligands, counterions, and additives on Lewis acidity is quantified and correlated to reaction yield at an early time point as an approximation for catalytic activity/efficiency and chelation mode in two organic transformations. Binding studies were performed under catalytically relevant conditions, giving further applicability to synthesis. Insight into activation modes are revealed through this analysis.

The association between network centrality and standard of living in a historical agrarian population.

OBJECTIVE: The aim of this study is to investigate the relationship between network centrality and living standards as measured by fertility and mortality responses to short-term economic stress. METHODS: Cox proportional hazard models estimate the effects of staple grain price variation and eigenvector and beta centrality within marriage and labor networks on the timing of births and child mortality (1-14 years) in a historical demographic data set from North Orkney, Scotland, 1851-1911. RESULTS: Households that are peripheral to the marriage and labor network experience lower chances of a birth when food prices are high. The fertility of more central households is less sensitive to price changes. A similar, but weaker, pattern holds for child mortality, which is also sensitive to price fluctuations, although the social gradient is not as clear. CONCLUSIONS: Marriage and labor network centrality is an indicator of standard of living in this remote, agricultural population. Households that are firmly embedded in the network are able to overcome and adjust to short-term economic stress without demographic consequences, while those at the edges of the community experience delayed reproduction in poor years consistent with unplanned responses to stress.

Interdisciplinary Approach to Spatiotemporal Population Dynamics: The North Orkney Population History Project.

The North Orkney Population History Project is a multidisciplinary data collection, digitization, and analysis effort that aims to reconstruct longitudinal demographic, environmental, and economic change. We describe the motivation, methodological approach, data sources, and some initial findings of the project. Detailed contextual information about a single community allows for the joint analysis of the changing population and changing landscape. The combination of diverse data sources and disciplinary approaches has resulted in findings that would not have been possible if each source had been considered in isolation. The approach adopted by the project offers a way to examine the interaction of a population with its landscape over a period of change.

Neutralizing Antibody Responses following Long-Term Vaccination with HIV-1 Env gp140 in Guinea Pigs.

A vaccination regimen capable of eliciting potent and broadly neutralizing antibodies (bNAbs) remains an unachieved goal of the HIV-1 vaccine field. Here, we report the immunogenicity of longitudinal prime/boost vaccination regimens with a panel of HIV-1 envelope (Env) gp140 protein immunogens over a period of 200 weeks in guinea pigs. We assessed vaccine regimens that included a monovalent clade C gp140 (C97ZA012 [C97]), a tetravalent regimen consisting of four clade C gp140s (C97ZA012, 459C, 405C, and 939C [4C]), and a tetravalent regimen consisting of clade A, B, C, and mosaic gp140s (92UG037, PVO.4, C97ZA012, and Mosaic 3.1, respectively [ABCM]). We found that the 4C and ABCM prime/boost regimens were capable of eliciting greater magnitude and breadth of binding antibody responses targeting variable loop 2 (V2) over time than the monovalent C97-only regimen. The longitudinal boosting regimen conducted over more than 2 years increased the magnitude of certain tier 1 NAb responses but did not increase the magnitude or breadth of heterologous tier 2 NAb responses. These data suggest that additional immunogen design strategies are needed to induce broad, high-titer tier 2 NAb responses.IMPORTANCE The elicitation of potent, broadly neutralizing antibodies (bNAbs) remains an elusive goal for the HIV-1 vaccine field. In this study, we explored the use of a long-term vaccination regimen with different immunogens to determine if we could elicit bNAbs in guinea pigs. We found that longitudinal boosting over more than 2 years increased tier 1 NAb responses but did not increase the magnitude and breadth of tier 2 NAb responses. These data suggest that additional immunogen designs and vaccination strategies will be necessary to induce broad tier 2 NAb responses.

First-in-Human Randomized, Controlled Trial of Mosaic HIV-1 Immunogens Delivered via a Modified Vaccinia Ankara Vector.

Background: Mosaic immunogens are bioinformatically engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains. Methods: This phase 1, double-blinded, randomized, placebo-controlled trial enrolled healthy HIV-uninfected adults who received 2 doses of a modified vaccinia Ankara (MVA)-vectored HIV-1 bivalent mosaic immunogen vaccine or placebo on days 0 and 84. Two groups were enrolled: those who were HIV-1 vaccine naive (n = 15) and those who had received an HIV-1 vaccine (Ad26.ENVA.01) 4-6 years earlier (n = 10). We performed prespecified blinded cellular and humoral immunogenicity analyses at days 0, 14, 28, 84, 98, 112, 168, 270, and 365. Results: All 50 planned vaccinations were administered. Vaccination was safe and generally well tolerated. No vaccine-related serious adverse events occurred. Both cellular and humoral cross-clade immune responses were elicited after 1 or 2 vaccinations in all participants in the HIV-1 vaccine-naive group. Env-specific responses were induced after a single immunization in nearly all subjects who had previously received the prototype Ad26.ENVA.01 vaccine. Conclusions: No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited. Clinical Trials Registration: NCT02218125.

Inequality and demographic response to short-term economic stress in North Orkney, Scotland, 1855-1910: Sector differences.

We examine economic inequality and social differences in infant and child mortality, and fertility responses to food price changes in North Orkney, 1855-1910, using linked vital records. This small population featured a diverse occupational structure, limited land resources, and geographic isolation from mainland Scotland. Segments of Orkney's non-agricultural working population were living so close to the margin of subsistence in normal years that an increase in food prices in bad years cost the lives of their children. Delayed childbearing, in addition to increased labour intensity, occupational diversification, and poor relief, failed to mitigate the negative effects of unfavourable prices in this group. While previous studies for Western Europe show a strong social gradient in mortality responses to food prices, and for Eastern Asia a strong household gradient, this study shows a strong sectoral gradient, indicating low standards of living for the non-agricultural working population well into the twentieth century.

Climate and marriage in the Netherlands, 1871-1937.

Environmental factors such as climate variability can place significant constraints on demographic behavior in a range of settings. However, few studies investigate the relationships between demography and climate in historical contexts. Using longitudinal individual-level demographic data from the Historical Sample of the Netherlands (HSN) and climate and economic data from 1871-1937, we examine the effects of climate variability on marriage. This analysis reveals that marriage increases with negative environmental conditions such as cold temperatures, riverine flooding, and high rye prices. These findings are not consistent with a Malthusian narrative of marriage behavior, or with the expectation that environmental constraints were stronger in the historical past.

Lanthanum(III)-Catalyzed Three-Component Reaction of Coumarin-3-carboxylates for the Synthesis of Indolylmalonamides and Analysis of Their Photophysical Properties.

New methodology has been developed for the Lewis acid catalyzed synthesis of malonamides. First, the scandium(III)-catalyzed addition of diverse nucleophiles (e.g., indoles, N,N-dimethyl-m-anisidine, 2-ethylpyrrole, and 2-methylallylsilane) to coumarin-3-carboxylates has been developed to afford chromanone-3-carboxylates in high yields as a single diastereomer. Upon investigating a subsequent lanthanum(III)-catalyzed amidation reaction, a new multicomponent reaction was designed by bringing together coumarin-3-carboxylates with indoles and amines to afford indolylmalonamides, which were identified to exhibit fluorescent properties. The photophysical properties for selected compounds have been analyzed, including quantum yield, molar absorptivity, and Stokes shift. Synthetic studies of several reaction byproducts involved in the network of reaction equilibria for the three-component reaction provide mechanistic insight for the development of this methodology.

Climate Variability and Human Migration in the Netherlands, 1865-1937.

Human migration is frequently cited as a potential social outcome of climate change and variability, and these effects are often assumed to be stronger in the past when economies were less developed and markets more localized. Yet, few studies have used historical data to test the relationship between climate and migration directly. In addition, the results of recent studies that link demographic and climate data are not consistent with conventional narratives of displacement responses. Using longitudinal individual-level demographic data from the Historical Sample of the Netherlands (HSN) and climate data that cover the same period, we examine the effects of climate variability on migration using event history models. Only internal moves in the later period and for certain social groups are associated with negative climate conditions, and the strength and direction of the observed effects change over time. International moves decrease with extreme rainfall, suggesting that the complex relationships between climate and migration that have been observed for contemporary populations extend into the nineteenth century.

Household demography and early childhood mortality in a rice-farming village in Northern Laos.

This paper extends Alexandr Chayanov's model of changing household demography (specifically the ratio of food consumers to food producers) and its influence on agricultural behavior so that it includes possible adverse effects of a rising ratio on nutritional status and early childhood mortality within the household. We apply the model to 35 years' worth of longitudinal demographic and economic data collected in the irrigated-rice growing village of Na Savang in northern Laos. When appropriate controls are included for other household variables, unobserved inter-household heterogeneity, and changes in local conditions and national policy over the study period, the analysis suggests that a unit increase in the household's consumer/producer ratio induces something like a nine-fold increase in the risk of death among household members aged less than five years. Monte Carlo simulation studies suggest that this may be an over-estimate but also that the effect is probably real and likely to be an important factor in household demography. At the very least, the results suggest that Chayanov's model still has theoretical relevance and deserves to be revived.

Effect of a computerized brain exercise program on cognitive performance in older adults.

OBJECTIVES: Research indicates an association between stimulating mental activities and better memory performance as people age, but studies on computerized mental stimulation programs are limited. We explored whether computerized brain training exercises improved cognitive performance in older adults. METHODS: In local retirement communities, a convenience sample was randomized into an intervention group (N = 36), who used a computer program 5 days a week for 20-25 minutes each day, or a wait-list control group (N = 33). All were older adults without dementia (mean age: 81.8 years; SD: 6.1; 67% female). Neuropsychological testing was completed at baseline (Time 1), 2 months (Time 2), and 6 months (Time 3). Three cognitive domains (Immediate Memory, Delayed Memory, Language) were compared in the two groups as a function of time using mixed models. RESULTS: The intervention group used the computerized program (Brain Fitness, Dakim Inc., Santa Monica, CA) for an average of 43 (SD: 4.4) sessions by Time 2 and 81 (SD: 37.5) sessions by Time 3. Mixed models examining cognitive domains as function of time revealed significant group differences in Delayed Memory (F(2,72) = 4.7, p = 0.01) but not Immediate Memory and Language; no significant improvements were noted for the control group. Among all participants, anyone playing at least 40 sessions over the 6 months improved in all three domains (Immediate Memory, Delayed Memory, and Language). CONCLUSION: Participating in a computerized brain exercise program over 6 months improves cognitive abilities in older adults. These results extend literature indicating the benefit of training exercises, whether in a classroom format or via a computerized self-paced program.

Differences in intergenerational fertility associations by sex and race in Saba, Dutch Caribbean, 1876-2004.

This study examines the intergenerational transmission of fertility behavior in Saba, Dutch Caribbean from 1876 to 2004 using reconstituted genealogies. Pearson product-moment correlation coefficients of several fertility measures and event-history models of age at first birth are used to explore relationships between the fertility of mothers and their children. The strength of intergenerational fertility ties varies by race and gender. Individuals that are better positioned to realize their fertility preferences have the strongest intergenerational associations, while individuals with the most limited reproductive options have the weakest intergenerational associations. This evidence supports hypotheses that posit the intergenerational transmission of attitudes, goals, and behaviors and the ability to act on those preferences as drivers of the presence or magnitude of links between the fertility of parents and their children.