Just in case: undergraduate students identifying and mitigating barriers to their sexual and reproductive health needs.

BACKGROUND: Many U.S. colleges and universities offer access to a healthcare center that provides sexual and reproductive health (SRH) resources, services, and products. The importance of health centers in college and university settings in reducing sexual health disparities in student populations cannot be stressed enough. This article evaluates a student-led, mutual-aid, grassroots health promotion strategy for students with limited access to healthcare services, supplies, and tools via an anonymous and discrete distribution of SRH resources without charge. METHODS: In partnership with faculty, undergraduate students worked to address their school's unmet SRH needs by increasing on-campus access to comprehensive, evidence-based, and sex-positive resources. Referred to as Just in Case, this student-led, grassroots health promotion program provided students with supply kits containing contraceptives, sexual health wellness products, basic hygiene supplies, and education materials. Students were surveyed in a pre- (n = 95) post- (n = 73) pilot study to identify contraception acquisition barriers, discern perceptions of on-campus SRH resources, and elucidate trends in this program's use and impact. Chi-square tests of independence were used to compare survey group responses, and association rule mining was employed in tandem to identify SRH items that students requested. RESULTS: Students identified cost and privacy as significant barriers to acquiring sexual health products on campus. Of the 182 Just in Case supply kits requested by students during the 2022-2023 academic year, condoms were requested most frequently in 75% of fulfilled kits, while emergency contraception and pregnancy tests were asked most often in 61% of kits. 50% of students reported access to contraceptives on campus before this program's implementation, growing to 75% (p < 0.001) 1 year later post-implementation. Similar jumps were observed for reported access to sexual health education (30 to 73%, p < 0.001) and services (36 to 73%, p < 0.001). CONCLUSION: A student-led SRH supply and resource delivery strategy may immediately reduce SRH inequities and decrease barriers to contraceptive use for students with limited access to on-site SRH product availability.

Integrated Multi-omics Analysis of Early Lung Adenocarcinoma Links Tumor Biological Features with Predicted Indolence or Aggressiveness.

Lung adenocarcinoma (LUAD) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate the biological determinants of early LUAD indolence or aggressiveness using radiomics as a surrogate of behavior. We present a set of 92 patients with LUAD with data collected across different methodologies. Patients were risk-stratified using the CT-based Score Indicative of Lung cancer Aggression (SILA) tool (0 = least aggressive, 1 = most aggressive). We grouped the patients as indolent (x ≤ 0.4, n = 14), intermediate (0.4 > x ≤ 0.6, n = 27), and aggressive (0.6 > x ≤ 1, n = 52). Using Cytometry by time of flight (CyTOF), we identified subpopulations with high HLA-DR expression that were associated with indolent behavior. In the RNA sequencing (RNA-seq) dataset, pathways related to immune response were associated with indolent behavior, while pathways associated with cell cycle and proliferation were associated with aggressive behavior. We extracted quantitative radiomics features from the CT scans of the patients. Integrating these datasets, we identified four feature signatures and four patient clusters that were associated with survival. Using single-cell RNA-seq, we found that indolent tumors had significantly more T cells and less B cells than aggressive tumors, and that the latter had a higher abundance of regulatory T cells and Th cells. In conclusion, we were able to uncover a correspondence between radiomics and tumor biology, which could improve the discrimination between indolent and aggressive LUAD tumors, enhance our knowledge in the biology of these tumors, and offer novel and personalized avenues for intervention. Significance: This study provides a comprehensive profiling of LUAD indolence and aggressiveness at the biological bulk and single-cell levels, as well as at the clinical and radiomics levels. This hypothesis generating study uncovers several potential future research avenues. It also highlights the importance and power of data integration to improve our systemic understanding of LUAD and to help reduce the gap between basic science research and clinical practice.

Effects of Respite Music on Repeated Upper-body Resistance Exercise Performance.

The purpose of this study was to investigate the effects of self-selected respite music on upper-body resistance exercise performance. In a crossover, counterbalanced study design, resistance-trained males (n = 10) participated in two bench press trials each with a different condition: 1) No music (NM), 2) Listening to respite music (RM; i.e. during rest periods). Following a warm-up, participants completed 3 sets × repetitions to failure (RTF) at 75% of 1-RM separated by 2 minutes of rest. During the 2-minute rest, participants either listened to NM or RM until the next subsequent set. A linear position transducer was used to measure mean barbell velocity during the first 3 repetitions and averaged for analysis. Rate of perceived exertion (RPE) and motivation were obtained after each set. Results indicate that mean velocity was higher during set 2 (p = 0.009; d = 1.34) and set 3 (p = 0.048; d = 0.95) while listening to RM versus NM. Furthermore, motivation was significantly higher following set 2 (p = 0.005; d = 1.15) and set 3 (p < 0.001; d = 1.79) while listening to RM compared to NM. No changes in RTF or RPE were noted between conditions (p > 0.05). These findings indicate listening to music during recovery may enhance subsequent explosive resistance performance and suggest that listening to music in between bouts of maximal effort could be an effective tool for optimizing performance during competition or training.

HLA-DR cancer cells expression correlates with T cell infiltration and is enriched in lung adenocarcinoma with indolent behavior.

Lung adenocarcinoma (ADC) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate whether CyTOF identifies cellular and molecular predictors of tumor behavior. We developed and validated a CyTOF panel of 34 antibodies in four ADC cell lines and PBMC. We tested our panel in a set of 10 ADCs, classified into long- (LPS) (n = 4) and short-predicted survival (SPS) (n = 6) based on radiomics features. We identified cellular subpopulations of epithelial cancer cells (ECC) and their microenvironment and validated our results by multiplex immunofluorescence (mIF) applied to a tissue microarray (TMA) of LPS and SPS ADCs. The antibody panel captured the phenotypical differences in ADC cell lines and PBMC. LPS ADCs had a higher proportion of immune cells. ECC clusters (ECCc) were identified and uncovered two ADC groups. ECCc with high HLA-DR expression were correlated with CD4+ and CD8+ T cells, with LPS samples being enriched for those clusters. We confirmed a positive correlation between HLA-DR expression on ECC and T cell number by mIF staining on TMA slides. Spatial analysis demonstrated shorter distances from T cells to the nearest ECC in LPS. Our results demonstrate a distinctive cellular profile of ECC and their microenvironment in ADC. We showed that HLA-DR expression in ECC is correlated with T cell infiltration, and that a set of ADCs with high abundance of HLA-DR+ ECCc and T cells is enriched in LPS samples. This suggests new insights into the role of antigen presenting tumor cells in tumorigenesis.

A Phase 1-2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC.

INTRODUCTION: This open-label, phase 1-2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). METHODS: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. RESULTS: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. CONCLUSIONS: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

Expanding Access to Lung Cancer Clinical Trials by Reducing the Use of Restrictive Exclusion Criteria: Perspectives of a Multistakeholder Working Group.

Low rates of adult patient participation have been a persistent problem in cancer clinical trials and have continued to be a barrier to efficient drug development. The routine use of significant exclusion criteria has contributed to this problem by limiting participation in studies and creating significant clinical differences between the study cohorts and the real-world cancer patient populations. These routine exclusions also unnecessarily restrict opportunities for many patients to access potentially promising new therapies during clinical development. Multiple efforts are underway to broaden eligibility criteria, allowing more patients to enroll in studies and generating more robust data regarding the effect of novel therapies in the population at large. Focusing specifically on lung cancer as an example, a multistakeholder working group empaneled by the LUNGevity Foundation identified 14 restrictive and potentially outdated exclusion criteria that appear frequently in lung cancer clinical trials. As a part of the project, the group evaluated data from multiple recent lung cancer studies to ascertain the extent to which these 14 criteria appeared in study protocols and played a role in excluding patients (screen failures). The present report describes the working group's efforts to limit the use of these routine exclusions and presents clinical justifications for reducing the use of 14 criteria as routine exclusions in lung cancer studies, potentially expanding trial eligibility and improving the generalizability of the results from lung cancer trials.

New Approaches to SCLC Therapy: From the Laboratory to the Clinic.

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.

In-Plane Vibration of Hammerhead Resonators for Chemical Sensing Applications.

Thermally excited and piezoresistively detected in-plane cantilever resonators have been previously demonstrated for gas- and liquid-phase chemical and biosensing applications. In this work, the hammerhead resonator geometry, consisting of a cantilever beam supporting a wider semicircular "head", vibrating in an in-plane vibration mode, is shown to be particularly effective for gas-phase sensing with estimated limits of detection in the sub-ppm range for volatile organic compounds. This paper discusses the hammerhead resonator design and the particular advantages of the hammerhead geometry, while also presenting mechanical characterization, optical characterization, and chemical sensing results. These data highlight the distinct advantages of the hammerhead geometry over other cantilever designs.

Scale-insensitive estimation of speed and distance traveled from animal tracking data.

BACKGROUND: Speed and distance traveled provide quantifiable links between behavior and energetics, and are among the metrics most routinely estimated from animal tracking data. Researchers typically sum over the straight-line displacements (SLDs) between sampled locations to quantify distance traveled, while speed is estimated by dividing these displacements by time. Problematically, this approach is highly sensitive to the measurement scale, with biases subject to the sampling frequency, the tortuosity of the animal's movement, and the amount of measurement error. Compounding the issue of scale-sensitivity, SLD estimates do not come equipped with confidence intervals to quantify their uncertainty. METHODS: To overcome the limitations of SLD estimation, we outline a continuous-time speed and distance (CTSD) estimation method. An inherent property of working in continuous-time is the ability to separate the underlying continuous-time movement process from the discrete-time sampling process, making these models less sensitive to the sampling schedule when estimating parameters. The first step of CTSD is to estimate the device's error parameters to calibrate the measurement error. Once the errors have been calibrated, model selection techniques are employed to identify the best fit continuous-time movement model for the data. A simulation-based approach is then employed to sample from the distribution of trajectories conditional on the data, from which the mean speed estimate and its confidence intervals can be extracted. RESULTS: Using simulated data, we demonstrate how CTSD provides accurate, scale-insensitive estimates with reliable confidence intervals. When applied to empirical GPS data, we found that SLD estimates varied substantially with sampling frequency, whereas CTSD provided relatively consistent estimates, with often dramatic improvements over SLD. CONCLUSIONS: The methods described in this study allow for the computationally efficient, scale-insensitive estimation of speed and distance traveled, without biases due to the sampling frequency, the tortuosity of the animal's movement, or the amount of measurement error. In addition to being robust to the sampling schedule, the point estimates come equipped with confidence intervals, permitting formal statistical inference. All the methods developed in this study are now freely available in the ctmmR package or the ctmmweb point-and-click web based graphical user interface.

Somatostatin receptor 2 targeting in small cell lung carcinoma: perspectives.

Small Cell lung carcinoma (SCLC) is the most lethal and aggressive subtype of lung cancer. Novel targeting approaches and agents are desperately needed. In this perspectives, we briefly explore recent data published in the International Journal of Cancer suggesting Somatostatin Receptor 2 (SSTR2) as a viable target for SCLC, summarize the current clinical trial space, and describe promising new research and clinical directions for Somatostatin Receptor 2 targeting in SCLC.

Author Correction: Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.

Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspectives article, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.

Somatostatin receptor 2 signaling promotes growth and tumor survival in small-cell lung cancer.

Somatostatin receptor 2 (SSTR2) is overexpressed in a majority of neuroendocrine neoplasms, including small-cell lung carcinomas (SCLCs). SSTR2 was previously considered an inhibitory receptor on cell growth, but its agonists had poor clinical responses in multiple clinical trials. The role of this receptor as a potential therapeutic target in lung cancer merits further investigation. We evaluated the expression of SSTR2 in a cohort of 96 primary tumors from patients with SCLC and found 48% expressed SSTR2. Correlation analysis in both CCLE and an SCLC RNAseq cohort confirmed high-level expression and identified an association between NEUROD1 and SSTR2. There was a significant association with SSTR2 expression profile and poor clinical outcome. We tested whether SSTR2 expression might contribute to tumor progression through activation of downstream signaling pathways, using in vitro and in vivo systems and downregulated SSTR2 expression in lung cancer cells by shRNA. SSTR2 downregulation led to increased apoptosis and dramatically decreased tumor growth in vitro and in vivo in multiple cell lines with decreased AMPKα phosphorylation and increased oxidative metabolism. These results demonstrate a role for SSTR2 signaling in SCLC and suggest that SSTR2 is a poor prognostic biomarker in SCLC and potential future therapeutic signaling target.

Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope.

Small cell lung cancer (SCLC) is a devastating and aggressive neuroendocrine carcinoma of the lung. It accounts for ~15% of lung cancer mortality and has had no improvement in standard treatment options for nearly 30 years. However, there is now hope for change with new therapies and modalities of therapy. Immunotherapies and checkpoint inhibitors are entering clinical practice, selected targeted therapies show promise, and "smart bomb"-based drug/radioconjugates have led to good response in early clinical trials. Additionally, new research insights into the genetics and tumor heterogeneity of SCLC alongside the availability of new tools such as patient-derived or circulating tumor cell xenografts offer the potential to shine light on this beshadowed cancer.

68Ga-DOTATATE PET/CT imaging of indeterminate pulmonary nodules and lung cancer.

PURPOSE: 18F-FDG PET/CT is widely used to evaluate indeterminate pulmonary nodules (IPNs). False positive results occur, especially from active granulomatous nodules. A PET-based imaging agent with superior specificity to 18F-FDG for IPNs, is badly needed, especially in areas of endemic granulomatous nodules. Somatostatin receptors (SSTR) are expressed in many malignant cells including small cell and non-small cell lung cancers (NSCLCs). 68Ga-DOTATATE, a positron emitter labeled somatostatin analog, combined with PET/CT imaging, may improve the diagnosis of IPNs over 18F-FDG by reducing false positives. Our study purpose was to test this hypothesis in our region with high endemic granulomatous IPNs. METHODS: We prospectively performed 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT scans in the same 30 patients with newly diagnosed, treatment-naïve lung cancer (N = 14) or IPNs (N = 15) and one metastatic nodule. 68Ga-DOTATATE SUVmax levels at or above 1.5 were considered likely malignant. We analyzed the scan results, correlating with ultimate diagnosis via biopsy or 2-year chest CT follow-up. We also correlated 68Ga-DOTATATE uptake with immunohistochemical (IHC) staining for SSTR subtype 2A (SSTR2A) in pathological specimens. RESULTS: We analyzed 31 lesions in 30 individuals, with 14 (45%) being non-neuroendocrine lung cancers and 1 (3%) being metastatic disease. McNemar's result comparing the two radiopharmaceuticals (p = 0.65) indicates that their accuracy of diagnosis in this indication are equivalent. 68Ga-DOTATATE was more specific (94% compared to 81%) and less sensitive 73% compared to 93%) than 18F-FDG. 68Ga-DOTATATE uptake correlated with SSTR2A expression in tumor stroma determined by immunohistochemical (IHC) staining in 5 of 9 (55%) NSCLCs. CONCLUSION: 68Ga-DOTATATE and 18F-FDG PET/CT had equivalent accuracy in the diagnosis of non-neuroendocrine lung cancer and 68Ga-DOTATATE was more specific than 18F-FDG for the diagnosis of IPNs. IHC staining for SSTR2A receptor expression correlated with tumor stroma but not tumor cells.

Single cell analysis of human tissues and solid tumors with mass cytometry.

BACKGROUND: Mass cytometry measures 36 or more markers per cell and is an appealing platform for comprehensive phenotyping of cells in human tissue and tumor biopsies. While tissue disaggregation and fluorescence cytometry protocols were pioneered decades ago, it is not known whether established protocols will be effective for mass cytometry and maintain cancer and stromal cell diversity. METHODS: Tissue preparation techniques were systematically compared for gliomas and melanomas, patient derived xenografts of small cell lung cancer, and tonsil tissue as a control. Enzymes assessed included DNase, HyQTase, TrypLE, collagenase (Col) II, Col IV, Col V, and Col XI. Fluorescence and mass cytometry were used to track cell subset abundance following different enzyme combinations and treatment times. RESULTS: Mechanical disaggregation paired with enzymatic dissociation by Col II, Col IV, Col V, or Col XI plus DNase for 1 h produced the highest yield of viable cells per gram of tissue. Longer dissociation times led to increasing cell death and disproportionate loss of cell subsets. Key markers for establishing cell identity included CD45, CD3, CD4, CD8, CD19, CD64, HLA-DR, CD11c, CD56, CD44, GFAP, S100B, SOX2, nestin, vimentin, cytokeratin, and CD31. Mass and fluorescence cytometry identified comparable frequencies of cancer cell subsets, leukocytes, and endothelial cells in glioma (R = 0.97), and tonsil (R = 0.98). CONCLUSIONS: This investigation establishes standard procedures for preparing viable single cell suspensions that preserve the cellular diversity of human tissue microenvironments. © 2016 International Clinical Cytometry Society.

Role of epidermal primary cilia in the homeostasis of skin and hair follicles.

Skin and hair follicle morphogenesis and homeostasis require the integration of multiple signaling pathways, including Hedgehog (Hh) and Wingless (Wnt), and oriented cell divisions, all of which have been associated with primary cilia. Although studies have shown that disrupting dermal cilia causes follicular arrest and attenuated Hh signaling, little is known about the role of epidermal cilia. Here, epidermal cilia function was analyzed using conditional alleles of the ciliogenic genes Ift88 and Kif3a. At birth, epidermal cilia mutants appeared normal, but developed basaloid hyperplasia and ingrowths into the dermis of the ventrum with age. In addition, follicles in the tail were disorganized and had excess sebaceous gland lobules. Epidermal cilia mutants displayed fewer long-term label-retaining cells, suggesting altered stem cell homeostasis. Abnormal proliferation and differentiation were evident from lineage-tracing studies and showed an expansion of follicular cells into the interfollicular epidermis, as is seen during wound repair. These phenotypes were not associated with changes in canonical Wnt activity or oriented cell division. However, nuclear accumulation of the ΔNp63 transcription factor, which is involved in stratification, keratinocyte differentiation and wound repair, was increased, whereas the Hh pathway was repressed. Intriguingly, the phenotypes were not typical of those associated with loss of Hh signaling but exhibited similarities with those of mice in which ΔNp63 is overexpressed in the epidermis. Collectively, these data indicate that epidermal primary cilia may function in stress responses and epidermal homeostasis involving pathways other than those typically associated with primary cilia.

Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts.

Cell motility and migration play pivotal roles in numerous physiological and pathophysiological processes including development and tissue repair. Cell migration is regulated through external stimuli such as platelet-derived growth factor-AA (PDGF-AA), a key regulator in directional cell migration during embryonic development and a chemoattractant during postnatal migratory responses including wound healing. We previously showed that PDGFRalpha signaling is coordinated by the primary cilium in quiescent cells. However, little is known about the function of the primary cilium in cell migration. Here we used micropipette analysis to show that a normal chemosensory response to PDGF-AA in fibroblasts requires the primary cilium. In vitro and in vivo wound healing assays revealed that in ORPK mouse (IFT88(Tg737Rpw)) fibroblasts, where ciliary assembly is defective, chemotaxis towards PDGF-AA is absent, leading to unregulated high speed and uncontrolled directional cell displacement during wound closure, with subsequent defects in wound healing. These data suggest that in coordination with cytoskeletal reorganization, the fibroblast primary cilium functions via ciliary PDGFRalpha signaling to monitor directional movement during wound healing.

An essential role for dermal primary cilia in hair follicle morphogenesis.

The primary cilium is a microtubule-based organelle implicated as an essential component of a number of signaling pathways. It is present on cells throughout the mammalian body; however, its functions in most tissues remain largely unknown. Herein we demonstrate that primary cilia are present on cells in murine skin and hair follicles throughout morphogenesis and during hair follicle cycling in postnatal life. Using the Cre-lox system, we disrupted cilia assembly in the ventral dermis and evaluated the effects on hair follicle development. Mice with disrupted dermal cilia have severe hypotrichosis (lack of hair) in affected areas. Histological analyses reveal that most follicles in the mutants arrest at stage 2 of hair development and have small or absent dermal condensates. This phenotype is reminiscent of that seen in the skin of mice lacking Shh or Gli2. In situ hybridization and quantitative RT-PCR analysis indicates that the hedgehog pathway is downregulated in the dermis of the cilia mutant hair follicles. Thus, these data establish cilia as a critical signaling component required for normal hair morphogenesis and suggest that this organelle is needed on cells in the dermis for reception of signals such as sonic hedgehog.