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Farhana Ibrahim and Tanuja Kothiyal, eds. 2021. South Asian Borderlands: Mobility, History, Affect. Cambridge: Cambridge University Press. x + 286 pp. Maps, tables, figures, notes, references, index. £75.00 (hardback)

This article (part of a special section on South Asian border studies) is an exploration of a multi-religious ethnic group in the borderland district of Poonch in Jammu and Kashmir, India. The work focuses on the Pahari ethnicity and looks at how prominent religious identities within this group have been continuously aligning themselves along religious lines in the post-partition era. Partition of the Indian subcontinent in 1947 acted as a major disruption in the construction of identities. The evolution of national and ethnic identities went hand in hand with the evolution of religious identities, with the latter being more pronounced than the former. Such a fixation along religious lines in the socio-cultural and political sphere led to changes in everyday inter-community relations. Through oral histories and other accounts, this ethnography understands the new set of interactions that emerged in Poonch which have been shaping identities, while also analysing identity construction and its impact on the social organisation of space and neighbourhoods in general in the post-partition era. Key Words: Borderland, Border, Boundaries, Community, Communalism, Difference, Ethnicity, Identity, Inter-community interaction, Nation, Nation-State, Othering, Religion

Introduction: Candida is the most important fungal opportunistic pathogen, though it is a normal commensal ora then also it can cause infections in the immunocompromised hosts. As non-albicans Candida have replaced Candida albicans as the predominant pathogen which is more life- threatening, more resistant to antifungal drugs so speciation of Candida is important. To identify & speciate Candida isolates fromObjective: various clinical samples and to nd out their antifungal susceptibility pattern. Samples were screened for budding yeastMaterial and method: cells with the help of Gram stain & KOH mount and then inoculated on SDA with gentamycin and chloramphenicol. For speciation, Germ tube testing was done followed by CHROM agar and chlamydospores on Cornmeal agar. Out of 100 Candida isolates, 19 were CandidaResults: albicans and 81 were non-albicans Candida. Among four antifungals tested, Amphotericin B showed the best efcacy with 83% strains sensitive to it and uconazole showed the least efcacy with 47% strains resistant to it. Though Candida albicans and non-albicans Candida areConclusion: closely related but differ from each other with respect to epidemiology, virulence factors, and antifungal susceptibility. As non-albicans Candida is more life-threatening and more resistant to antifungal agents; speciation of Candida becomes mandatory so that mortality and morbidity of the patients can be overcome.

Aberrant expression of P68 RNA helicase (p68), a prototypical member of the DEAD box family of RNA helicases, contributes to tumor development and progression. P68 tyrosine phosphorylation induced by PDGF signaling facilitates cancer metastasis by promoting EMT. In this report, we show that p68 promotes breast cancer cell EMT and cell migration by upregulation of PDGF receptor β (PDGFR-β). Knockdown of p68 in MDA-MB-231 and BT549 cells significantly decreases PDGFR-β both in mRNA and protein levels. P68 promotes EMT and cell migration in response to PDGF-BB stimulation via upregulation of PDGFR-β, suggesting that p68 enhances PDGF signaling by a positive feedback loop in cancer cells. Furthermore, our study reveals that p68 mediates the effects of PDGFR-β in regulation of androgen receptor (AR) in breast cancer cells. We demonstrate that p68 and PDGFR-β co-regulate AR expression and promote androgen-mediated proliferation in breast cancer cells. Our studies uncover an important pathway of p68-PDGFR-β axis in promoting breast cancer progression.

Marginalization based on geographic-isolation has serious repercussions on construction of identities. Identities in geographically isolated borderlands in Jammu and Kashmir are doubly-marginalized...

BACKGROUND Artificial Intelligence (AI) is often heralded as a potential disruptor that will transform the way we do medicine. The amount of data collected and available in health care, coupled with advances in computational power, have contributed to advances in AI and an exponential growth of publications. However, the development of AI applications does not guarantee their adoption into routine practice. There is a risk that despite the resources invested, benefits for patients, staff and society will not be realized if AI implementation is not better understood. OBJECTIVE The aim of this study was to explore how the implementation of AI in healthcare practice has been described and researched in the literature by answering three questions: 1. What are the characteristics of research on implementation of AI in practice? 2. What types and applications of AI systems are described? 3. What characteristics of the implementation process for the AI systems are discernable? METHODS A scoping review was conducted of Medline (PubMed), Scopus, Web of Science, CINAHL, and PsychInfo databases to identify empirical studies of AI implementation in healthcare since 2011 in addition to snowball sampling of selected reference lists. Titles and abstracts were screened and full-text articles using Rayyan.ai software. Data from the included articles was charted and summarized. RESULTS Of the 9218 records retrieved, forty-five articles were included. Most articles were published recently, from high-income countries, cover diverse clinical settings and disciplines, and intended for care-providers. AI systems are predominantly intended for clinical care, particularly clinical care pertaining to patient-provider encounters. Most possess no action autonomy, but rather support human decision-making. The focus of most research is on establishing the effectiveness of interventions, or related to technical and computational aspects of AI systems. Focus on the specifics of implementation processes does not yet seem to be a priority in research and the use of frameworks to guide implementation is rare. CONCLUSIONS Our current empirically knowledge derives from implementations of AI systems with low action autonomy and approaches common to other types of information systems. To develop a specific and empirically-based implementation framework, further research is needed on the more disruptive types of AI systems being implemented into routine care and on aspects unique to AI implementation in health care, such as building trust, addressing transparency issues, developing explainable and interpretable solutions and addressing ethical concerns around privacy and data protection.

The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA, HER2 and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, inhibitors of components of the pathway have only modest antitumor effects and, in some instances, have resulted in “tumor flares” in patients upon cessation of therapy. Low efficacy has been attributed to toxicity and to adaptive resistance due to relief of feedback. Inhibition of the PI3K pathway has been associated with increased receptor expression and decreased expression of the PTEN phosphatase, a major negative regulator of the pathway. Now we show that changes in expressions of RTKs, PTEN, anti-apoptosis proteins like Mcl1, and transcription factors known to drive oncogenic and survival programs in tumors like c-Myc, c-Jun, FOXOs are induced upon continuous long-term PI3K inhibition (2 weeks and longer). These changes increase as a function of duration of inhibition and become less reversible with time in drug. Unbiased clustering of RNA seq data of cells treated with PI3K inhibitors revealed clusters of gene expression changes based upon short or long-term inhibition. Correspondingly the mRNA of the RTKs and transcription factors change with similar kinetics as that of the proteins and become less reversible with duration of inhibition. Moreover, the persister cells treated with PI3K inhibitors for 2 weeks or longer grow faster than the treatment naive cells upon drug removal both in vitro and in vivo and the degree of reversibility of the increased proliferation rate is inversely proportional to the duration of inhibition. Persister cells treated with PI3K inhibitors for more than two weeks have higher levels of expression of a oncogenic transcription factors, RTKs, Mcl1, and of pAKT after one week of drug wash-out and are less sensitive to re-inhibition of PI3K. However, combined and staggered inhibition of PI3K with Mcl1/Bcl2 inhibitors lead to greater reduction of cell survival and increased cell death selectively in the models that upregulate Mcl1 in response to PI3K inhibitors. The data suggests that induction of adaptive resistance is in part responsible for the continued persistence of tumor masses after the initial response to targeted therapy but also selectively sensitizes them towards Mcl1/Bcl2 inhibitors due to the upregulation of an anti-apoptotic program. Therefore, pulsatile targeted inhibition of PI3K in combination with anti-apoptotic BH3 domain protein inhibitors in a subset of breast cancer patients may provide a wide therapeutic window and can circumvent chronic adaptation induced resistance and drive potent cell death thereby improving therapeutic outcomes. Citation Format: Radha Mukherjee, Kiran Gireesan Vanaja, Malvika Sharma, Yangjingyi Ruan Ruan, Hilla Solomon, Elisa deStanchina, Sarat Chandarlapaty, Neal Rosen. tumor adaptations to PI3K inhibition increases and its reversibility decreases as a function of time in drug. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3882.

I explore issues of identity and belonging in the field as a woman researcher, through encounters and narratives that highlight vulnerabilities in doing ethnography in a hostile borderland in Jammu and Kashmir. The contested notions of belonging – as a woman and as a researcher in the field – often proves challenging for female researchers who have to be mindful of both these identities at the same time. The field constantly reminds ‘the researcher’ of her identity as a woman, and here lies the difficult task of carrying out the fieldwork while remaining true to both. The challenges that a woman researcher faces can be overcome if she finds a way to negotiate her belonging in the field with herself, and with her participants.

Being an Ethnic-Pahari-Sikh-Borderlander in Poonch, Jammu and Kashmir is a phenomenon that adds to the discourse of ethnicity and nationalism. Partition of the Indian sub-continent in 1947 acted as...

Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapeutics owing to dense fibrotic stroma orchestrated by cancer-associated pancreatic stellate cells (CAPaSC). CAPaSC also support cancer cell growth, metastasis, and resistance to apoptosis. Currently, there is no effective therapy for PDAC that specifically targets CAPaSC. We previously reported a rationally designed protein, ProAgio, that targets integrin αvβ3 at a novel site and induces apoptosis in integrin αvβ3-expressing cells. Because both CAPaSC and angiogenic endothelial cells express high levels of integrin αvβ3, we aimed to analyze the effects of ProAgio in PDAC tumor. Methods Expression of integrin αvβ3 was examined in both patient tissue and cultured cells. The effects of ProAgio on CAPaSC were analyzed using an apoptosis assay kit. The effects of ProAgio in PDAC tumor were studied in 3 murine tumor models: subcutaneous xenograft, genetic engineered (KrasG12D; p53R172H; Pdx1-Cre, GEM-KPC) mice, and an orthotopic KrasG12D; p53R172H; Pdx1-Cre (KPC) model. Results ProAgio induces apoptosis in CAPaSC. ProAgio treatment significantly prolonged survival of a genetically engineered mouse–KPC and orthotopic KPC mice alone or in combination with gemcitabine (Gem). ProAgio specifically induced apoptosis in CAPaSC, resorbed collagen, and opened collapsed tumor vessels without an increase in angiogenesis in PDAC tumor, enabling drug delivery into the tumor. ProAgio decreased intratumoral insulin-like growth factor 1 levels as a result of depletion of CAPaSC and consequently decreased cytidine deaminase, a Gem metabolism enzyme in cancer cells, and thereby reduced resistance to Gem-induced apoptosis. Conclusions Our study suggests that ProAgio is an effective PDAC treatment agent because it specifically depletes CAPaSC and eliminates tumor angiogenesis, thereby enhancing drug delivery and Gem efficacy in PDAC tumors., Graphical abstract

Background: Village health sanitation and nutrition day (VHSND) was conceived under the National Rural Health Mission to deliver maternal and child health and nutrition services at the village level in the anganwadi center. Multiple challenges, including a lack of convergence of frontline workers, were affecting service delivery at VHSND. As a public–private partnership Piramal Foundation proposed to revive the concept of VHSND. Objectives: The present study was aimed to demonstrate a model of VHSND to provide primary care related to maternal and child health and nutrition at the village level in 25 aspirational districts across seven states of India. Methods: The descriptive study was undertaken as a pilot phase. Of the purposively identified 506 VHSND sites, monitoring data on delivery of six basic primary care services at VHSND, collected as part of routine operations were compared for 229 sites for the month of September 2018 (baseline) and January 2019 (endline). Results: In model sites, there was the increased availability of drinking water and functional toilets; a significant improvement of availability of equipment for providing antenatal care services, immunization, and growth monitoring. However, the supply of drugs at these sites did not show a statistically significant change. There was also a significant improvement in the engagement of the Village Health Sanitation and Nutrition Committee (VHSNC) in the villages of the model VHSND sites. Conclusion: The model demonstrated the significant changes with effective supervision and participation of VHSNC members, demand generation activities complemented with improved supplies and widening range of services at the VHSND are required to be undertaken.

Chronic Liver Diseases (CLD) are characterized by abnormal accumulation of collagen fibrils, neo-angiogenesis, and sinusoidal remodeling. Collagen deposition along with intrahepatic angiogenesis and sinusoidal remodeling alters sinusoid structure resulting in portal hypertension, liver failure, and other complications. Efforts were made to develop treatments for CLDs. However, the success of such treatments is limited and unpredictable. We report a strategy for CLD treatment by induction of integrin αvβ3 mediated cell apoptosis using a rationally designed protein (ProAgio). ProAgio is designed to target integrin αvβ3 at a novel site. Integrin αvβ3 is highly expressed in activated Hepatic Stellate Cells (HSC), angiogenic endothelium, and capillarized Liver Sinusoidal Endothelial Cells (LSEC). ProAgio induces apoptosis of these disease causative cells. Tests with liver fibrosis mouse models demonstrate that ProAgio reverses liver fibrosis and relieves blood flow resistance by depleting activated HSC and capillarized LSEC. Our studies demonstrate an effective approach for CLD treatment., As activated hepatic stellate cells and liver sinusoidal endothelial cells express high levels of integrin α v β3, Turaga et al. present a strategy for treatment of chronic liver disease using their rationally designed protein (ProAgio) which targets integrin α v β3. They find that ProAgio –mediated apoptosis of these disease-associated cells reverses liver fibrosis and ameliorates intrahepatic vascular resistance in a mouse model

Early diagnosis and noninvasive detection of liver fibrosis and its heterogeneity remain as major unmet medical needs for stopping further disease progression toward severe clinical consequences. Here we report a collagen type I targeting protein-based contrast agent (ProCA32.collagen1) with strong collagen I affinity. ProCA32.collagen1 possesses high relaxivities per particle (r1 and r2) at both 1.4 and 7.0 T, which enables the robust detection of early-stage (Ishak stage 3 of 6) liver fibrosis and nonalcoholic steatohepatitis (Ishak stage 1 of 6 or 1 A Mild) in animal models via dual contrast modes. ProCA32.collagen1 also demonstrates vasculature changes associated with intrahepatic angiogenesis and portal hypertension during late-stage fibrosis, and heterogeneity via serial molecular imaging. ProCA32.collagen1 mitigates metal toxicity due to lower dosage and strong resistance to transmetallation and unprecedented metal selectivity for Gd3+ over physiological metal ions with strong translational potential in facilitating effective treatment to halt further chronic liver disease progression. Non-invasive early diagnosis of liver fibrosis is important to prevent disease progression and direct treatment strategies. Here the authors developed a collagen-targeting contrast agent for the detection of early stage fibrosis and non-alcoholic steatohepatitis by magnetic resonance and tested it in animal models.

Despite reports of successful clinical cases, many tumors appear to resist infection by oncolytic viruses (OVs). To circumvent this problem, an armed vesicular stomatitis virus was constructed by inserting a transgene to express Smac/DIABLO during virus infection (VSV-S). Endogenous Smac in HeLa cells was diminished during wtVSV infection, whereas the Smac level was enhanced during VSV-S infection. Apoptosis was readily induced by VSV-S, but not wtVSV, infection. More importantly, the tumor volume was reduced to a larger extent when xenografts of 4T1 cells in BALB/c mice and OV-resistant T-47D cells in nude mice were intratumorally injected with VSV-S. VSV-S represents a novel mechanism to overcome tumor resistance, resulting in more significant tumor regression due to enhanced apoptosis.

Increased levels of nitrate (NO3-) in the environment can be detrimental to human health. Herein, we report a robust, cost-effective, and scalable, hybrid material-based colorimetric/luminescent sensor technology for rapid, selective, sensitive, and interference-free in situ NO3- detection. These hybrid materials are based on a square-planar platinum(II) salt [Pt(tpy)Cl]PF6 (tpy = 2,2';6',2″-terpyridine) supported on mesoporous silica. The platinum salt undergoes a vivid change in color and luminescence upon exposure to aqueous NO3- anions at pH ≤ 0 caused by substitution of the PF6- anions by aqueous NO3-. This change in photophysics of the platinum salt is induced by a rearrangement of its crystal lattice that leads to an extended Pt···Pt···Pt interaction, along with a concomitant change in its electronic structure. Furthermore, incorporating the material into mesoporous silica enhances the surface area and increases the detection sensitivity. A NO3- detection limit of 0.05 mM (3.1 ppm) is achieved, which is sufficiently lower than the ambient water quality limit of 0.16 mM (10 ppm) set by the United States Environmental Protection Agency. The colorimetric/luminescence of the hybrid material is highly selective to aqueous NO3- anions in the presence of other interfering anions, suggesting that this material is a promising candidate for the rapid NO3- detection and quantification in practical samples without separation, concentration, or other pretreatment steps.

During a health emergency such as the current COVID-19 (coronavirus disease 2019) pandemic, immediate access to validated information is of utmost importance. Unfortunately, unverified, unreliable, and speculative information flows at an unprecedented rate in today's world, leading to an "infodemic." In such a scenario, Indian states have used telephone-based health helplines to provide an effective channel for the provision of validated, accurate, and up-to-date information. We analyzed the utilization of these helplines for providing COVID-19-related information and the profile of callers handled by these helplines across 8 states of India. These helplines received more than 6.4 million calls over a period of 6 months. The volume of calls mirrored key announcements and events taking place in India as a response to the pandemic, such as the nation-wide lockdown, extension of lockdown, and so on. Nearly three quarters of the callers belonged to the economically productive age group of 20 to 59 years. The majority of the callers were males across all 8 states. The proportion of female callers was lowest in Bihar and highest in the small, hill state of Sikkim.

Sharma et al. present a treatment strategy by simultaneously depleting breast cancer CAFs and tumor angiogenic vessels using a rationally designed protein that induces integrin αvβ3 target-specific cell apoptosis. This offers a unique opportunity for TNBC treatment, especially for patients with dense tumor stroma., Fibrotic tumor stroma plays an important role in facilitating triple-negative breast cancer (TNBC) progression and chemotherapeutic resistance. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces apoptosis via the integrin. Cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in TNBC tumor express high levels of integrin αvβ3. ProAgio effectively induces apoptosis in CAFs and aECs. The depletion of CAFs by ProAgio reduces intratumoral collagen and decreases growth factors released from CAFs in the tumor, resulting in decreased cancer cell proliferation and apoptotic resistance. ProAgio also eliminates leaky tumor angiogenic vessels, which consequently reduces tumor hypoxia and improves drug delivery. The depletion of CAFs and reduction in hypoxia by ProAgio decreases lysyl oxidase (LOX) secretion, which may play a role in the reduction of metastasis. ProAgio stand-alone or in combination with a chemotherapeutic agent provides survival benefit in TNBC murine models, highlighting the therapeutic potential of ProAgio as a treatment strategy., Graphical Abstract

Approximately 1% of primary care office visits are for chest pain, and 2% to 4% of these patients will have unstable angina or myocardial infarction. Initial evaluation is based on determining whether the patient needs to be referred to a higher level of care to rule out acute coronary syndrome (ACS). A combination of age, sex, and type of chest pain can predict the likelihood of coronary artery disease as the cause of chest pain. The Marburg Heart Score and the INTERCHEST clinical decision rule can also help estimate ACS risk. Twelve-lead electrocardiography is recommended to look for ST segment changes, new-onset left bundle branch block, presence of Q waves, and new T-wave inversions. Patients with suspicion of ACS or changes on electrocardiography should be transported immediately to the emergency department. Those at low or intermediate risk of ACS can undergo exercise stress testing, coronary computed tomography angiography, or cardiac magnetic resonance imaging. In those with low suspicion for ACS, consider other diagnoses such as chest wall pain or costochondritis, gastroesophageal reflux disease, and panic disorder or anxiety states. Other less common, but important, diagnostic considerations include acute pericarditis, pneumonia, heart failure, pulmonary embolism, and acute thoracic aortic dissection.

Introduction While inadequate sleep is known to increase inflammation in immunocompetent individuals, it is unknown if poor sleep worsens inflammation in people living with HIV. The ratio of CD4+/CD8+ T cells is a readily derived measure of chronic inflammation in people living with HIV. We sought to investigate the association between lymphocyte subsets and actigraphy-derived sleep measures in a cohort of HIV seropositive men. Methods HIV seropositive men on antiretroviral therapy for > 1 year and with undetectable (< 20 copies/mL) plasma HIV-1 RNA participating in the Multicenter AIDS Cohort Study underwent a sleep evaluation with 1 week of wrist actigraphy. Data from 287 participants with ≥ 5 days of actigraphy were analyzed. We evaluated three dimensions of sleep: mean nocturnal sleep duration, sleep onset latency, and sleep maintenance efficiency. Linear regression was used to assess the association between each sleep dimension with CD4+ and CD8+ T-cell counts. Because of a U-shaped association, nocturnal sleep duration was also modelled dichotomously as a normal (6-8 hrs) vs. abnormal duration (8 hrs). Results Participants had a mean (±SD) age of 55 ± 12 years, mean CD4+ count of 723 ± 293 cells/ml, and 7.0 ± 1.7 days of actigraphy data. None of the sleep measures were associated with CD4+ counts. However, participants with abnormal sleep duration had 129 ± 31 cells/mL higher CD8+ counts compared to those with normal sleep duration (p=0.01). There were also nonsignificant trends whereby every 30-minute increase in sleep latency was associated with a 138 cells/ml increase in CD8+ count (p=0.07) while every 10% reduction in sleep efficiency was associated with a 56 cells/ml increase in CD8+ count (p=0.12). These findings were unchanged after adjusting for age and body mass index. Conclusion Among men with treated HIV infection, abnormal sleep duration (both short and long) is associated with increased circulating CD8+ T cell count, suggesting increased chronic inflammation. Support (If Any) NIH AI0355041, HL082610 and American Thoracic Society ASPIRE Fellowship

Red crystals of [Pt(tpy)Cl]NO3·HNO3 show mechanochromic behaviour turning yellow when pressure is applied. The electronic character and spectroscopic signature of the red and yellow polymorphs change as a result of slipping of the molecular stacking planes in the solid state. The slippage alters the PtPt intermolecular distances from a linear stacked motif with

The MRI (Magnetic Resonance Imaging) is diagnosis tool for detection of tumor in brain as it uses magnets to produce magnetic field and radio waves to generate images of brain and also used to analyse it. The abnormal growth of cells or tissues is known as tumor, the presence of tumor can be detected by help MR images. The use of digital image processing is to be done in order to analysis the MR image. The various techniques of image processing such as image acquisition, pre-processing, feature extraction, image classification etc. are utilized for analysis of magnetic images. The segmentation is one of the technique that partition digital image into multiple segments .it is used to locate the lines, curves and objects in the image. The survey of various techniques that are based on segmentation of MR images are to be done in this paper.

To address the need for a field-deployable in-situ technique for the accurate and reliable detection of organic contaminants in water, this work reports a new chemical sensing approach for the detection of aqueous MeCN. The approach relies on the reversible colorimetric/luminescent change in a transition metal complex. In this approach, a square planar platinum salt [Pt(tpy)Cl](PF6) (tpy = 2,2′:6′,2″-terpyridine) demonstrated a reversible color change from yellow to red as well as a red shift in emission intensity upon exposure to aqueous MeCN. This observed spectroscopic change was induced by the incorporation of MeCN molecules withing the crystal lattice of the platinum salt, that resulted in an enhancement in the intermolecular Pt•••Pt interactions, which correlatively altered the electronic structure. The spectroscopic response was highly selective and quantitative for aqueous MeCN. This work illustrates a new technique for the rapid, selective, sensitive detection of aqueous MeCN, while also providing a general strategy for the detection of other small molecule contaminants.

Pulmonary Sarcomatoid Carcinoma (PSC) is a poorly differentiated NSCLC with sarcoma like differentiation (spindle/giant cell) or a component of sarcoma (malignant bone/cartilage/skeletal muscle). WHO grading 2015, classifies sarcomatoid ca into five histological types: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma.

Background: Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of cancer owing to its insensitivity to many chemotherapeutic drugs. Gemcitabine remains a cornerstone of PDA treatment despite suboptimal efficacy in clinics. One major mechanism by which PDA becomes resistant to gemcitabine is its conversion to inactive derivative, dFdU by upregulation of the enzyme, cytidine deaminase (Cda) in cancer cells. Activated pancreatic stellate cells (PSC) are the major source of IGF1 in the tumor microenvironment, which may be responsible for an increase in Cda expression in cancer cells. We previously reported a rationally designed protein, ProAgio that targets integrin αVβ3 at a novel site. Here we demonstrate that ProAgio specifically induces apoptosis of integrin αVβ3-expressing activated PSC and therefore circumvents gemcitabine resistance in murine PDA models. Objective: To test whether targeting activated PSC restores chemotherapeutic sensitivity in previously unresponsive PDA tumors in a murine model. Methods: To study the effect of ProAgio and gemcitabine combination in PDA, we used two murine PDA models: a) KP orthotopic mouse model where KPC cells were orthotopically injected into the pancreas and, b) LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mouse model. Mice were treated with 20 doses of ProAgio (10mg/kg; i.p.) and 10 doses of gemcitabine twice weekly (50mg/kg; i.p.). IGF1 and Cda levels were analyzed by ELISA and immunohistochemistry. The intratumoral levels of the gemcitabine prodrug 2′,2′-difluorodeoxcytidine (dFdC) and the inactivated and activated metabolites (2′,2′-difluorodeoxyuridine (dFdU) and gemcitabine triphosphate (dFdCTP) respectively were determined by LCMS. Results: Our data in murine PDA models clearly demonstrate that pharmacological targeting of activated PSC by ProAgio can stabilize PDA, and when combined with gemcitabine significantly increased the survival benefit by 3-fold (p Citation Format: Ravi Chakra Turaga, Malvika Sharma, Falguni Mishra, Zhi-Ren Liu. Pharmacological targeting of activated PSC decreases resistance to gemcitabine and increases survival in murine PDA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 117.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a five-year survival rate of just 9% after diagnosis. Despite large efforts in developing treatments, the outcome of therapies for patient survival only improves marginally. Dense fibrotic stroma and ECM orchestrated by cancer-associated pancreatic stellate cells (CAPaSC) is considered to be one of the major contributors of resistance to anti-tumor therapies in this disease. The presence of dense collagen fibrils forms a physical block to drug delivery and the completely collapsed intratumoral blood vessels lead to poor blood perfusion resulting in treatment failure. CAPaSC also engage in symbiotic “cross-talk” with cancer cells through cytokines, growth factors, and chemokines supporting cancer cell growth, survival, and resistance to apoptosis. In turn, cancer cells provide factors that support pancreatic stellate cells (PaSC) proliferation and survival. PaSC upon activation express high levels of integrin αVβ3. We previously reported the development of a protein, ProAgio that targets integrin αVβ3 at a novel site and induces apoptosis of integrin αVβ3 expressing cells. We demonstrate here that ProAgio specifically induces apoptosis of CAPaSC and reduces collagen in the pancreatic tumor, enabling delivery of drug molecules into the tumor. Objective: To test whether targeting CAPaSC reduces the pathological progression of PDAC in murine models. Methods: We examined the effects of ProAgio in vitro and in a xenograft mouse model in vivo wherein Panc-1 cells were co-implanted with immortalized and activated human PaSC. Further, we used two murine PDAC models: a) Genetically engineered mouse (GEM) KPC model, and, b) KP orthotopic mouse model where KPC cells were orthotopically injected into the pancreas. Mice were treated with 20 doses of ProAgio (10mg/kg; i.p.). Tumor histological analysis was performed. Drug diffusion was measured by administering Fluor 595-conjugated goat IgG via tail vein. Results: PaSC promoted the growth of pancreatic cancer cells in vitro. Integrin αVβ3 is highly upregulated in CAPaSC and ProAgio effectively induced apoptosis of CAPaSC. ProAgio treatment markedly inhibited the tumor growth when Panc-1 cells were co-implanted with activated human PaSC. In more clinically relevant models, such as GEM KPC and KP orthotopic mouse models, ProAgio treatment exhibited around 60-70% decrease in α-SMA positive cells and intratumoral collagen levels. In addition, ProAgio treatment decompressed the intratumoral vessels without an increase in angiogenesis and significantly increased the delivery of drug into the tumor. In conclusion, our findings for the first time demonstrate that ProAgio may potentially be a unique agent that is capable of specifically depleting CAPaSC in PDAC to facilitate treatment. Citation Format: Malvika Sharma, Ravi Chakra Turaga, Falguni Mishra, Yi Yuan, Zhi-Ren Liu. Modulation of cancer-associated fibrotic stroma reduces pathological progression of PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 110.