To evaluate whether testing positive for human papillomavirus (HPV) before treatment is associated with cervical cancer recurrence and disease-free, cancer-specific, and overall survival and to report the relationship of HPV to cervical cancer histology, stage, grade, tumor size, lymph node involvement, and treatment response. EMBASE and MEDLINE were searched from inception to January 27, 2022, with the use of MeSH terms and keywords relating to cervical cancer, HPV, and prognosis. ClinicalTrials.gov was not searched because of the nature of our review question. Studies must have assessed HPV DNA or RNA in cervical pretreatment biopsies or cells from 20 or more patients with invasive cervical cancer followed up for any length of time and reported the effect of testing positive or negative for HPV on cervical cancer recurrence, disease-free survival, cancer-specific survival, or overall survival. We extracted data on HPV-detection methods, patient and tumor characteristics, and clinical outcomes. Hazard ratios (HRs) and 95% CIs were pooled with a random-effects model. Meta-regression was performed to explore heterogeneity. Of 11,179 titles or abstracts and 474 full-text articles reviewed, 77 studies were included in the systematic review. Among these 77 studies, 30 reported on the relationship of HPV status to histology, 39 to cancer stage, 13 to tumor grade, 17 to tumor size, 23 to lymph node involvement, and four to treatment response. Testing positive for HPV was associated with better disease-free survival (HR 0.38, 95% CI 0.25-0.57; 15 studies with 2,564 cases), cancer-specific survival (HR 0.56, 95% CI 0.44-0.71; nine studies with 1,398 cases), and overall survival (HR 0.59, 95% CI 0.47-0.74; 36 studies with 9,169 cases), but not recurrence (HR 0.59, 95% CI 0.33-1.07; eight studies with 1,313 cases). Meta-regression revealed that the number of cases, tumor grade, specimen type, gene target, and HPV prevalence together explained 73.8% of the between-study heterogeneity. This review indicates that HPV detectability in cervical cancer is associated with a better clinical prognosis. https://osf.io/dtyeb .

The assembly of complexes following the detection of extracellular signals is often controlled by signaling proteins comprising multiple peptide binding modules. The SRC homology (SH)3 family represents the archetypical modular protein interaction module, with ~300 annotated SH3 domains in humans that regulate an impressive array of signaling processes. We review recent findings regarding the allosteric contributions of SH3 domains host protein context, their phosphoregulation, and their roles in phase separation that challenge the simple model in which SH3s are considered to be portable domains binding to specific proline-rich peptide motifs.

High-dose rate (HDR) and pulsed-dose rate (PDR) brachytherapy would benefit from an independent treatment verification system to monitor treatment delivery and to detect errors in real time. This paper characterizes and provides an uncertainty budget for a detector based on a fiber-coupled high-Z inorganic scintillator capable of performing time-resolved in vivo dosimetry during HDR and PDR brachytherapy. The detector was composed of a detector probe and an optical reader. The detector probe consisted of either a 0.5× 0.4 × 0.4 mm3 (HDR) or a 1.0 × 0.4 × 0.4 mm3 (PDR) cuboid ZnSe:O crystal glued onto an optical-fiber cable. The outer diameter of the detector probes was 1mm, and fit inside standard brachytherapy catheters. The signal from the detector probe was read out at 20Hz by a photodiode and a data acquisition device inside the optical reader. In order to construct an uncertainty budget for the detector, six characteristics were determined: (1) temperature dependence of the detector probe, (2) energy dependence as a function of the probe-to-source position in 2D (determined with 2 mm resolution using a robotic arm), (3) the signal-to-noise ratio (SNR), (4) short-term stability over 8h, and (5) long-term stability of three optical readers and four probes used for in vivo monitoring in HDR and PDR treatments over 21 months (196 treatments and 189 detector calibrations, and (6) dose-rate dependence. The total uncertainty of the detector at a 20 mm probe-to-source distance was<5.1% and<5.8% for the HDR and PDR versions, respectively. Regarding the above characteristics, (1) the sensitivity of the detector decreased by an average of 1.4%/°C for detector probe temperatures varying from 22 to 37°C; (2) the energy dependence of the detector was nonlinear and depended on both probe-to-source distance and the angle between the probe and the brachytherapy source; (3) the median SNRs were 187 and 34 at a 20 mm probe-to-source distance for the HDR and PDR versions, respectively (corresponding median source activities of 4.8 and 0.56Ci, respectively); (4) the detector response varied by 0.6% in 11 identical irradiations over 8h; (5) the sensitivity of the four detector probes decreased systematically by 0-1.2%/100Gy of dose delivered to the probes, and random fluctuations of 4.8% in the sensitivity were observed for the three probes used in PDR and 1.9% for the probe used in HDR; and (6) the detector response was linear with dose rate. ZnSe:O detectors can be used effectively for in vivo dosimetry and with high accuracy for HDR and PDR brachytherapy applications.

Several in vitro and in vivo studies investigated the biological properties of mistletoe preparations [1-4]. In Europe, where phytochemical constituents of aqueous Viscum album extracts were previously described, the most widespread and common form of mistletoe is the white-berried species (Viscum album) [5]. The aim of the present study was to analyze the biological activity and phytochemical features of different Viscum album ssp mother tinctures collected in 2 different harvesting periods. &#x0D; &#x0D; Leaves, stems and berries of Viscum album samples were subjected to ethanolic extraction (45% v/v) following the homeopathic pharmacopeia [6,7]. The mother tinctures (MT) prepared were: V. album (from 3 host trees Malus domestica, Quercus sp, Ulmus sp), V. album ssp. austriacum (host tree Pinus sylvestris) and V. album ssp. abietis (host tree Abies pectinata). All samples were collected at Höfli farm (Switzerland) in July and August and subjected to chemical analysis by means of high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) and Thin-Layer Chromatography (TLC). Tumor (Yoshida and Molt4) and non-tumor cells (Ma104) were incubated with MT (1; 0.1; 0.01%) for 4, 24 and 48 hours at 37ºC. Proliferation was indirectly measured using WST-1 (tumor cells) and MTT (non-tumor cells). All cells (1.5 x 104/100 μL) were plated in triplicate in 96-well plates. The cell proliferation inhibition rate was calculated as percent inhibition relative to control cells treated with the MT solvent (45% ethanol v/v). Apoptosis/necrosis was measured using 2 x 105 cells incubated with Annexin V-FITC and 7-AAD at room temperature in the dark, and analyzed in flow cytometer [2]. Antimicrobial activity was assessed for Candida albicans, Cryptococcus neoformans, Escherichia coli and Staphylococcus aureus following the Clinical Laboratory Standards Institute manuals [8-9] and compared with 45% ethanol v/v (MT solvent).&#x0D; &#x0D; The chromatographic assays of MT samples showed phenolic acids and lignans as main chemical classes identified. WST-1 and MTT experiments revealed different antitumor potential of MT. In general, Yoshida cells were more sensitive than Molt4. The maximal cytotoxic effect with 100% of mortality was attained by incubation of Yoshida and Molt-4 cells with 1% MT of V. album ssp. abietis (harvested in July) for 4 hours. Preliminary results with non-tumor cells indicate lower cytotoxicity compared to tumor cells. Annexin V/7ADD showed predominance of late apoptotic/necrotic events after 4 and 24 hours of incubation with all MT. The antimicrobial assay showed that MT of Viscum album ssp. austriacum (host tree Pinus sylvestris) exhibited minimum inhibitory concentration 7.25 mg/mL for the 2 tested bacterial strains. &#x0D; &#x0D; The results of the present study suggest that Viscum album samples prepared according to the homeopathic pharmacopeia exhibit promising biological activities in a dose-dependent manner. The effects of potentiation will be assessed and compared to non-potentiated samples in future experiments. Therefore, the present study contributes with data on the main chemical components in homeopathic preparations of Viscum album, drawing attention to the relevance of extract solvent, seasonal aspects, host tree and harvested parts of plant harvested to the quality of thee mother tinctures.

Background: The mistletoe Viscum album L. (Santalaceae) is a semi-parasitic plant that grows on different host trees. Although V. album antitumor activity is mainly associated with aqueous preparations, recently we showed antitumoral effects of homeopathic V. album tinctures containing also the ethanolic soluble compounds [1]. &#x0D; Aims: to analyze the phytochemical profile of different Viscum album homeopathic tinctures as well as their in vitro effects in tumoral cells. &#x0D; Methodology: The Viscum album samples (leaves, stems and berries) were collected in 2016 and 2017 (summer), and in 2018 (winter) at different locations in Switzerland. After harvest, they were immediately submitted to ethanolic extraction (45% V/V) using homeopathic methodology [2, 3]. The following mother tinctures (MT) were prepared: V. album ssp. album growing on Malus domestica, Quercus sp. and Ulmus sp., V. album ssp. austriacum from Pinus sylvestris, and V. album ssp. abietis from Abies alba. The homeopathic dynamizations (1-3dH; 6, 12, 30dH) were prepared with the respective MT. The phytochemical profiles were analysed by High Performance Liquid Chromatography tandem Mass Spectroscopy, HPLC and Thin Layer Chromatography. MT prepared in 2016 were also submitted to the Pfeiffer’s circular chromatography (PCC) [4]. The proliferation assay was performed by WST-1 [5] after incubation of tumoral cells (Yoshida and Molt-4) with non-dynamized (0.5 to 0.05% v/v) and dynamized MT. Apoptosis/necrosis was measured by flow cytometer (FACS) using Annexin V-FITC [5], and the cellular morphological aspects were analysed by light microscope. &#x0D; Results and Discussion: The chemical analyses of MT identified the presence of phenolic acids, flavonoids, lignans, as principal compounds. Besides, the HPLC indicated higher viscotoxin concentration in the summer harvest of Abies alba, Malus domestica and Quercus (897, 475, 219 ?g/mL), respectively. The PCC methodology permitted the MT differentiation. The higher levels of cellular mortality were attribute to Abies alba, Malus domestica and Quercus (p

The poly(ADP-ribose) polymerase 1 (PARP-1) enzyme has received much attention in the last decade due to its promising role in cancer therapeutics. Despite the expanding use of PARP inhibitors in cancer therapy, little is known about PARP-1 tissue distribution. Our study provides a detailed survey of PARP-1 tissue and cellular distribution using well-preserved cynomolgus monkey organs and a well-characterized, highly specific monoclonal PARP-1 antibody. Overall, PARP-1 was detected in most organs, but its distribution was restricted to specific cells within each tissue, suggesting that PARP-1 expression is tightly regulated. The strongest expression was in the pituitary, the ovary, the male adrenal gland, and the thymus. One of the key findings of this study was the stronger expression of PARP-1 in proliferating cells rather than mature cells. This observation not only provides clues to the importance of PARP-1 in processes such as DNA replication and transcription in these cell types, but it also provides the basis for further investigation into the effects of its inhibition in the context of malignancy. Overall, this study greatly expands the current knowledge of PARP-1 tissue expression, enabling the identification of tissues where PARP inhibition may be most efficacious.

Primary mucinous carcinoma of the ovary is uncommon, and while numerous studies have focused on improving our ability to distinguish these tumors from gastrointestinal metastases, recent data suggest that up to one fifth are still misdiagnosed with a previously underrecognized culprit: endometrioid carcinoma. Using an index case of an ovarian endometrioid carcinoma with mucinous differentiation masquerading as a mucinous carcinoma, we sought to identify the most efficient biomarker combination that could distinguish these 2 histotypes. Eight immunohistochemical markers were assessed on tissue microarrays from 183 endometrioid carcinomas, 77 mucinous carcinomas, and 72 mucinous borderline tumors. Recursive partitioning revealed a simple 2-marker panel consisting of PR and vimentin. The combination of PR absence and vimentin absence could predict mucinous tumors with a sensitivity of 95.1%, a specificity of 96.7%, and an overall accuracy of 96.0%. Additional marker combinations did not improve accuracy. The 5-yr ovarian cancer-specific survival for mucinous carcinoma was significantly worse than endometrioid carcinoma (70% vs. 86%, respectively, P=0.02). Our proposed 2-marker algorithm allows diagnostic distinction between mucinous and endometrioid ovarian carcinomas when morphology is not straightforward. Given key differences in the underlying biology and clinical behavior of these 2 histotypes, improved diagnostic precision is essential for guiding appropriate management and treatment.

Ovarian carcinoma histotypes are critical for research and patient management and currently assigned by a combination of histomorphology +/- ancillary immunohistochemistry (IHC). We aimed to validate the previously described IHC algorithm (Calculator of Ovarian carcinoma Subtype/histotype Probability version 3, COSPv3) in an independent population-based cohort, and to identify problem areas for IHC predictions. Histotype was abstracted from cancer registries for eligible ovarian carcinoma cases diagnosed from 2002 to 2011 in Alberta and British Columbia, Canada. Slides were reviewed according to World Health Organization 2014 criteria, tissue microarrays were stained with and scored for the 8 COSPv3 IHC markers, and COSPv3 histotype predictions were calculated. Discordant cases for review and COSPv3 prediction were arbitrated by integrating morphology with IHC results. The integrated histotype (N=880) was then used to identify areas of inferior COSPv3 performance. Review histotype and integrated histotype demonstrated 93% agreement suggesting that IHC information revises expert review in up to 7% of cases. There was also 93% agreement between COSPv3 prediction and integrated histotype. COSPv3 errors predominated in 4 areas: endometrioid carcinoma (EC) versus clear cell (N=23), EC versus low-grade serous (N=15), EC versus high-grade serous (N=11), and high-grade versus low-grade serous (N=6). Most problems were related to Napsin A-negative clear cell, WT1-positive EC, and p53 IHC wild-type high-grade serous carcinomas. Although 93% of COSPv3 prediction accuracy was validated, some histotyping required integration of morphology with ancillary test results. Awareness of these limitations will avoid overreliance on IHC and misclassification of histotypes for research and clinical management.

Intraoperative dosimetry in low-dose-rate (LDR) permanent prostate brachytherapy requires accurate localization of the implanted seeds with respect to the prostate anatomy. Transrectal Ultrasound (TRUS) imaging, which is the main imaging modality used during the procedure, is not sufficiently robust for accurate seed localization. We present a method for integration of electromagnetic (EM) tracking into LDR prostate brachytherapy procedure by fusing it with TRUS imaging for seed localization. Experiments were conducted on five tissue mimicking phantoms in a controlled environment. The seeds were implanted into each phantom using an EM-tracked needle, which allowed recording of seed drop locations. After each needle, we reconstructed a 3D ultrasound (US) volume by compounding a series of 2D US images acquired during retraction of an EM-tracked TRUS probe. Then, a difference image was generated by nonrigid registration and subtraction of two consecutive US volumes. A US-only seed detection method was used to detect seed candidates in the difference volume, based on the signature of the seeds. Finally, the EM-based positions of the seeds were used to detect the false positives of the US-based seed detection method and also to estimate the positions of the missing seeds. After the conclusion of the seed implant process, we acquired a CT image. The ground truth for seed locations was obtained by localizing the seeds in the CT image and registering them to the US coordinate system. Compared to the ground truth, the US-only detection algorithm achieved a localization error mean of 1.7 mm with a detection rate of 85%. By contrast, the EM-only seed localization method achieved a localization error mean of 3.7 mm with a detection rate of 100%. By fusing EM-tracking information with US imaging, we achieved a localization error mean of 1.8 mm while maintaining a 100% detection rate without any false positives. Fusion of EM-tracking and US imaging for prostate brachytherapy can combine high localization accuracy of US-based seed detection with the robustness and high detection rate of EM-based seed localization. Our phantom experiments serve as a proof of concept to demonstrate the potential value of integrating EM-tracking into LDR prostate brachytherapy.