Immune checkpoint therapy-current perspectives and future directions.

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

A Perspective Review: Analyzing Collagen Alterations in Ovarian Cancer by High-Resolution Optical Microscopy.

High-grade serous ovarian cancer (HGSOC) is the predominant subtype of ovarian cancer (OC), occurring in more than 80% of patients diagnosed with this malignancy. Histological and genetic analysis have confirmed the secretory epithelial of the fallopian tube (FT) as a major site of origin of HGSOC. Although there have been significant strides in our understanding of this disease, early stage detection and diagnosis are still rare. Current clinical imaging modalities lack the ability to detect early stage pathogenesis in the fallopian tubes and the ovaries. However, there are several microscopic imaging techniques used to analyze the structural modifications in the extracellular matrix (ECM) protein collagen in ex vivo FT and ovarian tissues that potentially can be modified to fit the clinical setting. In this perspective, we evaluate and compare the myriad of optical tools available to visualize these alterations and the invaluable insights these data provide on HGSOC initiation. We also discuss the clinical implications of these findings and how these data may help novel tools for early diagnosis of HGSOC.

Evaluation of Collagen Alterations in Early Precursor Lesions of High Grade Serous Ovarian Cancer by Second Harmonic Generation Microscopy and Mass Spectrometry.

Background: The collagen architecture in high grade serous ovarian cancer (HGSOC) is highly remodeled compared to the normal ovary and the fallopian tubes (FT). We previously used Second Harmonic Generation (SHG) microscopy and machine learning to classify the changes in collagen fiber morphology occurring in serous tubal intraepithelial carcinoma (STIC) lesions that are concurrent with HGSOC. We now extend these studies to examine collagen remodeling in pure p53 signatures, STICs and normal regions in tissues that have no concurrent HGSOC. This is an important distinction as high-grade disease can result in distant collagen changes through a field effect mechanism. Methods: We trained a linear discriminant model based on SHG texture and image features as a classifier to discriminate the tissue groups. We additionally performed mass spectrometry analysis of normal and HGSOC tissues to associate the differential expression of collagen isoforms with collagen fiber morphology alterations. Results: We quantified the differences in the collagen architecture between normal tissue and the precursors with good classification accuracy. Through proteomic analysis, we identified the downregulation of single α-chains including those for Col I and III, where these results are consistent with our previous SHG-based supramolecular analyses. Conclusion: This work provides new insights into ECM remodeling in early ovarian cancer and suggests the combined use of SHG microscopy and mass spectrometry as a new diagnostic/prognostic approach.

Imaging Collagen Alterations in STICs and High Grade Ovarian Cancers in the Fallopian Tubes by Second Harmonic Generation Microscopy.

The majority of high-grade serous ovarian cancers originate in the fallopian tubes, however, the corresponding structural changes in the extracellular matrix (ECM) have not been well-characterized. This information could provide new insight into the carcinogenesis and provide the basis for new diagnostic tools. We have previously used the collagen-specific Second Harmonic Generation (SHG) microscopy to probe collagen fiber alterations in high-grade serous ovarian cancer and in other ovarian tumors, and showed they could be uniquely identified by machine learning approaches. Here we couple SHG imaging of serous tubal intra-epithelial carcinomas (STICs), high-grade cancers, and normal regions of the fallopian tubes, using three distinct image analysis approaches to form a classification scheme based on the respective collagen fiber morphology. Using a linear discriminant analysis, we achieved near 100% classification accuracy between high-grade disease and the other tissues, where the STICs and normal regions were differentiated with ~75% accuracy. Importantly, the collagen in high-grade disease in both the fallopian tube and the ovary itself have a similar collagen morphology, further substantiating the metastasis between these sites. This analysis provides a new method of classification, but also quantifies the structural changes in the disease, which may provide new insight into metastasis.

Characterization of vocalizations emitted in isolation by California mouse (Peromyscus californicus) pups throughout the postnatal period.

Rodent species, such as monogamous and biparental California mice, produce vocalizations as a means of communication. A temporal examination of vocalizations produced by California mice pups in isolation was performed. Pup recordings were performed for 3 min at ∼10.00 and 14.00 hrs on early postnatal days (PND) 2-4, 7, 21, and 28. Once initial recordings were finished, pups were returned to the home cage with parents and any siblings for 5 minutes to determine if active biparental responses resulted in an enhanced vocalization response when pups were isolated and retested. We also sought to determine whether potential reduction in vocalizations by older pups might be due to procedure-habituation procedure associated with less anxiety and/or possibly decreased need for parental care. Vocalizations were measured in weanling (30 days of age) "naïve" pups not previously isolated. Results show older pups took significantly longer to vocalize, indicated by increased latency before producing their initial syllable compared to earlier ages. With increasing age, pups demonstrated decreased syllable duration, reduced number and duration of phrases, and decreased number of syllables per phrase. No differences in pup vocalizations were observed before and after being placed back with parents, suggestive biparental potentiation may not exist in California mice pups. Comparison of the naïve to habituated weanling pups indicated the former group had more total calls but no other differences in vocalization parameters were detected between these 2 groups. Collectively, the findings suggest that as California mice pups mature and approach weaning they generally vocalize less in isolation. (PsycINFO Database Record