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About one-fourth of patients with pancreatic ductal adenocarcinoma (PDAC) are categorized as borderline resectable (BR) or locally advanced (LA). Chemotherapy and radiation therapy have not yielded the anticipated outcomes in curing patients with BR/LA PDAC. The surgical resection of these tumors presents challenges owing to the unpredictability of the resection margin, involvement of vasculature with the tumor, the likelihood of occult metastasis, a higher ratio of positive lymph nodes, and the relatively larger size of tumor nodules. Oncolytic virotherapy has shown promising activity in preclinical PDAC models. Unfortunately, the desmoplastic stroma within the PDAC tumor microenvironment establishes a barrier, hindering the infiltration of oncolytic viruses and various therapeutic drugs—such as antibodies, adoptive cell therapy agents, and chemotherapeutic agents—in reaching the tumor site. Recently, a growing emphasis has been placed on targeting major acellular components of tumor stroma, such as hyaluronic acid and collagen, to enhance drug penetration. Oncolytic viruses can be engineered to express proteolytic enzymes that cleave hyaluronic acid and collagen into smaller polypeptides, thereby softening the desmoplastic stroma, ultimately leading to increased viral distribution along with increased oncolysis and subsequent tumor size regression. This approach may offer new possibilities to improve the resectability of patients diagnosed with BR and LA PDAC.

Pancreatic Ductal Adenocarcinoma (PDAC) is projected to become the 2nd leading cause of cancer-related deaths in the United States. Limitations in early detection and treatment barriers contribute to the lack of substantial success in the treatment of this challenging-to-treat malignancy. Desmoplasia is the hallmark of PDAC microenvironment that creates a physical and immunologic barrier. Stromal support cells and immunomodulatory cells face aberrant signaling by pancreatic cancer cells that shifts the complex balance of proper repair mechanisms into a state of dysregulation. The product of this dysregulation is the desmoplastic environment that encases the malignant cells leading to a dense, hypoxic environment that promotes further tumorigenesis, provides innate systemic resistance, and suppresses anti-tumor immune invasion. This desmoplastic environment combined with the immunoregulatory events that allow it to persist serve as the primary focus of this review. The physical barrier and immune counterbalance in the tumor microenvironment (TME) make PDAC an immunologically cold tumor. To convert PDAC into an immunologically hot tumor, tumor microenvironment could be considered alongside the tumor cells. We discuss the complex network of microenvironment molecular and cellular composition and explore how they can be targeted to overcome immuno-therapeutic challenges.

Some evidence indicates that ischemic preconditioning (IPC) may positively affect endurance exercise performance, but IPC's effect on running performance is unclear. This study's purpose was to examine the effect of IPC on running performance in recreational runners. Participants (n=12) completed IPC, a sham (SH) condition, and a leg elevation without blood restriction (LE) control condition on separate days (order randomized). For IPC, blood was restricted using blood pressure cuffs inflated to 220 mmHg at the thigh. For SH, the cuffs were inflated to only 20 mmHg. For LE, participants positioned their legs at 90 degrees against a wall while laying supine. The duration of each protocol was 30 minutes (three 5-minute bouts with 5-minute breaks). Following each protocol, participants ran 2.4 kilometers as fast as possible on a motorized treadmill. Run time, heart rate, and perceived exertion were measured and statistically compared, using repeated-measures ANOVA, each 0.8 kilometers. There were no differences in heart rate or time trial performance across protocols (p>0.05; IPC, 612.5±61.2 sec; SH, 608.1±57.9 sec; LE, 612.7±59.1 sec). Rating of perceived exertion at 0.8 kilometers was significantly lower for the IPC protocol than SH in females only (~5.7%, or ~0.8 points on a 6-20 scale; p<0.05). Our IPC protocol did not improve running performance or physiological parameters during a time trial run in recreational runners. The performance benefit seen in this study's most fit individuals suggests that fitness level may influence IPC's efficacy for improving endurance running performance. [ABSTRACT FROM AUTHOR]

Abstract Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source–sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue‐engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. β‐Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace‐and‐drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation.

Theoretical cardiac electrophysiology focuses on the dynamics of the membrane and sarcoplasmic reticulum ion currents; however, passive (e.g., membrane capacitance) and quasi-active (response to small signals) properties of the cardiac sarcolemma, which are quantified by impedance, are also important in determining the behavior of cardiac tissue. Theoretically, impedance varies in the different phases of a cardiac cycle. Our goal in this study was to numerically predict and experimentally validate these phasic changes. We calculated the expected impedance signal using analytic methods (for generic ionic models) and numerical computation (for a rabbit ventricular ionic model). Cardiac impedance is dependent on the phase of the action potential, with multiple deflections caused by a sequential activation and inactivation of various membrane channels. The two main channels shaping the impedance signal are the sodium channel causing a sharp and transient drop at the onset of action potential and the inward rectifying potassium channel causing an increase in impedance during the plateau phase. This dip and dome pattern was confirmed in an ex-vivo rabbit heart model using high-frequency sampling through a monophasic action potential electrode. The hearts were immobilized using a myosin-inhibitor to minimize motion artifacts. We observed phasic impedance changes in three out of four hearts with a dome amplitude of 2 − 4Ω. Measurement of phasic impedance modulation using an extracellular electrode is feasible and provides a non-invasive way to gain insight into the state of cardiac cells and membrane ionic channels. The observed impedance recordings are consistent with the dip and dome pattern predicted analytically.

To increase confidence in the use of the beam method for the analysis of interior cylindrical shells and also provide data for those cases in which the beam method is not applicable, design constants for interior cylindrical shells based on the shell theory are presented. These constants enable the ready evaluation of the internal forces in shells by a few simple multiplica-tions. In addition studies on the effect of the geometry of the shell on the longitudinal distribution of stresses are included. A discussion of the effect of continuity enlarges the applicability of the design constants. [ABSTRACT FROM AUTHOR]

During the 19th century and for much of the 20th century, disease of the lower limb in diabetic patients was conceptualized not, as it is now, as 'the diabetic foot' or as 'a diabetic foot ulcer' but as 'gangrene in the diabetic foot' or as 'diabetic gangrene'. The prognostically and therapeutically important distinction between gangrene due to vascular insufficiency and gangrene due to infection in a limb with a normal or near normal blood supply was not made until about 1893. The advent of aseptic surgery improved the survival of amputation flaps, but surgery remained a hazardous undertaking until the discovery of insulin. Although insulin therapy reduced the risk of surgical intervention, diabetic foot disease now replaced hyperglycaemic coma as the major cause of diabetic mortality. The increasing workload attributable to diabetic foot disease after the introduction of insulin is reflected in the publications on diabetes in the 1920s. In some hospitals in North America this led to initiatives in prophylactic care and patient education, the importance of which were only more widely appreciated some 60 years later. A continuing emphasis on ischemia and infection as the major causes of diabetic foot disease led to a neglect of the role of neuropathy. In consequence, the management of diabetic neuropathic ulceration entered a prolonged period of therapeutic stagnation at a time when significant advances were being made in the management of lepromatous neuropathic ulceration. Reasons for the revival of progress in the management of diabetic neuropathic ulceration in the 1980s will be discussed. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the impact of the COVID-19 pandemic and vaccine perceptions on Human Papillomavirus (HPV) vaccine hesitancy. Secondary endpoints included comparing COVID-19 and HPV vaccination trends regarding time, community of residence, and unmet social needs., Methods: This was a survey-based, cross-sectional study that included 101 participants who were recruited through the Wyandotte County Public Health Department. Participants were eligible for inclusion in this study if they were a parent/guardian of one or more children aged 13 to 17; English- or Spanish-speaking. This study took place in Wyandotte County, Kansas. Descriptive statistics and chi-square analyses were utilized., Results: There was no difference in completion of COVID-19 and HPV vaccines (p = 0.0975). Significantly more individuals started and did not finish the HPV vaccine series compared to the COVID-19 vaccine series (p = 0.0004). Most participants indicated their opinion on the HPV vaccine had not changed due to the pandemic (71.3 %). Participants who felt familiar with HPV had higher rates of HPV vaccine completion. While 77 % of participants felt extremely or moderately familiar with HPV, 61.4 % were unaware of its association with oropharyngeal cancer., Conclusion: There was minimal change in parents' perception of the HPV vaccine due to the COVID-19 pandemic despite decreased rates of vaccination during this time. HPV vaccine series completion was significantly lower than COVID-19 vaccine series completion, highlighting a need to improve HPV vaccine completion counseling. Additionally, patient education should address the knowledge gap discovered regarding the link between HPV infection and oropharyngeal cancer., Competing Interests: Declaration of competing interest The authors have no conflicts of interest and no sources of support to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)