Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects

Pancreatic ductal adenocarcinoma (PDAC) is projected to emerge as the second leading cause of cancer-related death after 2030. Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC. To date, combination chemotherapy remains the mainstay of treatment for most PDAC patients. Compared to other cancer types, treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable and are drivers of treatment resistance, PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance. However, emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes. These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression. The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells, stromal fibroblasts, and immune cells. This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease. Here, we provide a concise review on lessons learned from past stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC

A case of intermittent left bundle branch block

An 82-year-old woman with uncontrolled hypertension and occasional exertional dyspnea was found to be in intermittent left bundle branch block (LBBB). Her laboratory results, echocardiogram, and ischemic workup were unremarkable. This case highlights that intermittent LBBB is not always associated with coronary ischemia, vasospasm, blunt cardiac injury, drugs, and high catecholaminergic or inflammatory states

Perceptions de la variabilité climati que et stratégies d’adaptation dans le système oasien de Gouré (Sud-est Niger)

Les savoirs liés au temps et à l’espace, et l’identification des stratégies paysannes pour affronter les problèmes climatiques sont indispensables pour toute compréhension des questions climatiques. Pour mieux apprécier les perceptions de la variabilité climatique et les stratégies d’adaptation utilisées, une enquête semi structuré qui a concerné 60 personnes repartie dans 4 villages du département de Gouré, situé dans l’Est du Niger est conduite selon une approche qualitative et quantitative. Les effets de la variabilité climatique ressentis par les agriculteurs sont l’aridité du climat, l’augmentation de la température et le caractère aléatoire des pluies. Les éleveurs la perçoivent de façon indirecte à travers la réduction du fourrage et de la disponibilité d’eau. Ces effets ont poussé ces populations à adopter des stratégies d’adaptation comme la recherche de nouvelles variétés à cycle court et supportant les poches de sécheresse, la pratique des techniques de fixation des dunes pour la restauration du couvert herbacé, l’utilisation de la fumure organique, la modification des dates de semis, le stockage de fourrage, le déstockage des animaux pendant la soudure, les prières collectives de demande de pluies. Elles sont toutefois insuffisantes du fait de la persistance des effets négatifs de la variabilité climatiques au Niger.Mots clés: Variabilité climatique, perception, stratégies d’adaptation, Gouré, NigerEnglish Title: Farmers perception and adaptation strategies to climate change in the oasis system of Goure (Southeast Niger)English AbstractKnowledge related to the perception of time and space, and identification of farmers’ strategies for dealing with climate change is a perequisite for a good understanding of climate issues. Farmers’ climate variability perceptions and adaptation strategies was studied using a survey conducted with sixty (60) farmers in the department of Gouré, located in eastern Niger. Results showed that farmers directly experience changes in  climate variability through temperature increase, frequent drought and erratic rainfall. By contrast, herders sense the effects of climate change indirectly through fodder reduction and scarce water availability. These effects have prompted farmers to adopt coping strategies such as the use of improved varieties, early and drought tolerant, sand dune stabilization and land reclamation, use of organic manure, changing of planting dates, storage of fodder, the destocking of animals during drought periods, collective prayers for rain. These strategies, however, appear to be insufficient for addressing the negative effects of climate change in this part of Niger.Keywords: climate variability, perception, strategies of adaptation, Goure, Nige

Discriminating early-stage diabetic retinopathy with subjective and objective perimetry

Introduction: To prevent progression of early-stage diabetic retinopathy, we need functional tests that can distinguish multiple levels of neural damage before classical vasculopathy. To that end, we compared multifocal pupillographic objective perimetry (mfPOP), and two types of subjective automated perimetry (SAP), in persons with type 2 diabetes (PwT2D) with either no retinopathy (noDR) or mild to-moderate non-proliferative retinopathy (mmDR). Methods: Both eyes were assessed by two mfPOP test methods that present stimuli within either the central ±15° (OFA15) or ±30° (OFA30), each producing per-region sensitivities and response delays. The SAP tests were 24-2 Short Wavelength Automated Perimetry and 24-2 Matrix perimetry. Results: Five of eight mfPOP global indices were significantly different between noDR and mmDR eyes, but none of the equivalent measures differed for SAP. Per-region mfPOP identified significant hypersensitivity and longer delays in the peripheral visual field, verifying earlier findings. Diagnostic power for discrimination of noDR vs. mmDR, and normal controls vs. PwT2D, was much higher for mfPOP than SAP. The mfPOP per-region delays provided the best discrimination. The presence of localized rather than global changes in delay ruled out iris neuropathy as a major factor. Discussion: mfPOP response delays may provide new surrogate endpoints for studies of interventions for early-stage diabetic eye damage.</p

Cascade screening for beta-thalassaemia in Pakistan: relatives’ experiences of a decision support intervention in routine practice

Low uptake of cascade screening for βeta-thalassaemia major (β-TM) in the ‘Punjab Thalassaemia Prevention Project’ (PTPP) in Pakistan led to the development of a ‘decision support intervention for relatives’ (DeSIRe). This paper presents the experiences of relatives of children with β-TM of the DeSIRe following its use by PTPP field officers (FOs) in routine clinical practice. Fifty-four semi-structured qualitative interviews were conducted (April to June 2021) with relatives in seven cities in the Punjab province (Lahore, Sheikhupura, Nankana Sahab, Kasur, Gujranwala, Multan and Faisalabad). Thematic analysis shows that participants were satisfied with the content of the DeSIRe and its delivery by the FOs in a family meeting. They understood that the main purpose of the DeSIRe was to improve their knowledge of β-TM and its inheritance, and to enable them to make decisions about thalassaemia carrier testing, particularly before marriage. Participants also raised concerns about the stigma of testing positive; however, they believed the DeSIRe was an appropriate intervention, which supported relatives to make informed decisions. Our findings show that the DeSIRe is appropriate for use by healthcare professionals in routine practice in a low-middle income country, and has the potential to facilitate shared decision making about cascade screening for thalassaemia. Further research is needed to prove the efficacy of the DeSIRe

The aspherical explosion of the Type IIP SN 2017gmr

Type IIP supernovae (SNe IIP), which represent the most common class of core-collapse (CC) SNe, show a rapid increase in continuum polarization just after entering the tail phase. This feature can be explained by a highly asymmetric helium core, which is exposed when the hydrogen envelope becomes transparent. Here we report the case of an SN IIP (SN 2017gmr) that shows an unusually early rise of the polarization, 30 d before the start of the tail phase. This implies that SN 2017gmr is an SN IIP that has very extended asphericity. The asymmetries are not confined to the helium core, but reach out to a significant part of the outer hydrogen envelope, hence clearly indicating a marked intrinsic diversity in the aspherical structure of CC explosions. These observations provide new constraints on the explosion mechanism, where viable models must be able to produce such extended deviations from spherical symmetry, and account for the observed geometrical diversity

Rapid Objective Testing of Visual Function Matched to the ETDRS Grid and Its Diagnostic Power in Age-Related Macular Degeneration

Purpose: To study the power of an 80-second multifocal pupillographic objective perimetry (mfPOP) test tailored to the ETDRS grid to diagnose age-related macular degeneration (AMD) by Age-Related Eye Disease Study (AREDS) severity grade. Design: Evaluation of a diagnostic technology. Methods: We compared diagnostic power of acuity, ETDRS grid retinal thickness data, new 80-second M18 mfPOP test, and two wider-field 6-minute mfPOP tests (Macular-P131, Widefield-P129). The M18 stimuli match the size and shape of bifurcated ETDRS grid regions, allowing easy structure–function comparisons. M18, P129, and P131 stimuli test both eyes concurrently. We recruited 34 patients with early-stage AMD with a mean ± standard deviation (SD) age of 72.6 ± 7.06 years. The M18 and P129 plus P131 stimuli had 26 and 51 control participants, respectively with mean ± SD ages of 73.1 ± 8.17 years and 72.1 ± 5.83 years, respectively. Multifocal pupillographic objective perimetry testing used the Food and Drug Administration-cleared Objective FIELD Analyzer (OFA; Konan Medical USA). Main Outcome Measures: Percentage area under the receiver operator characteristic curve (AUC) and Hedge's g effect size. Results: Acuity and OCT ETDRS grid thickness and volume produced reasonable diagnostic power (percentage AUC) for AREDS grade 4 eyes at 83.9 ± 9.98% and 90.2 ± 6.32% (mean ± standard error), respectively, but not for eyes with less severe disease. By contrast, M18 stimuli produced percentage AUCs from 72.8 ± 6.65% (AREDS grade 2) to 92.9 ± 3.93% (AREDS grade 4), and 82.9 ± 3.71% for all eyes. Hedge's g effect sizes ranged from 0.84 to 2.32 (large to huge). Percentage AUC for P131 stimuli performed similarly and for P129 performed somewhat less well. Conclusions: The rapid and objective M18 test provided diagnostic power comparable with that of wider-field 6-minute mfPOP tests. Unlike acuity or OCT ETDRS grid data, OFA tests produced reasonable diagnostic power in AREDS grade 1 to 3 eyes.</p