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Objective: To describe the gene alteration status in high-grade neuroendocrine cervical carcinoma (NECC) specimens and to explore the potential association of unique gene alterations with survival. Methods: Results from tumor-based molecular testing on specimens from women with high- grade NECC in the Neuroendocrine Cervical Tumor Registry were reviewed and analyzed. Tumor specimens could be from primary or metastatic sites and obtained at initial diagnosis, during treatment, or at recurrence. Results: Molecular testing results were available for 109 women with high-grade NECC. The genes most frequently mutated were PIK3CA (mutated in 18.5% of patients), TP53 (17.4%), and MYC (14.5%). Other targetable alterations identified were alterations in KIT (7.3%), KRAS (7.3%), and PTEN (7.3%). Women with tumors having an RB1 alteration (6.4%) had a median overall survival (OS) of 13 months, compared to 26 months for women with tumors that did not have an RB1 alteration (p=0.003). None of the other genes evaluated were shown to be associated with OS. Conclusion: Although no individual alteration was found in a majority of tumor specimens from patients with high-grade NECC, a large proportion of women with this disease will have at least one targetable alteration. Treatments based on these gene alterations may offer additional targeted therapies for women with recurrent disease, who currently have very limited therapeutic options. Patients with tumors that harbor RB1 alterations have decreased OS. [ABSTRACT FROM AUTHOR]

To address disparities in COVID-19 outcomes among Latinos with limited English proficiency in Maryland, our team developed a culturally congruent intervention that coupled a statewide social marketing campaign with community-based COVID-19 services. In the first year, we reached 305 122 people through social media advertisements and had 9607 visitors to the Web site. Social marketing campaigns represent an opportunity to promote COVID-19 testing and vaccine uptake among Latino populations, especially when they are paired with community services that simultaneously address structural barriers to care. (Am J Public Health. 2023;113(3):263–266. https://doi.org/10.2105/10.2105/AJPH.2022.307191) [ABSTRACT FROM AUTHOR]

To evaluate the disease course of patients with low grade endometrial stromal sarcoma (LG-ESS) and compare oncologic outcomes associated with hormonal therapy in primary and recurrent disease. This is a retrospective study of patients with LG-ESS who underwent active treatment between January 2000 and July 2023. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier product-limit estimator and modeled via Cox proportional hazards regression. A total of 221 patients were included; 58 % of patients (91/157) were stage I, 12 % (19/157) stage II, 13 % (20/157) stage III, and 17 % (27/157) stage IV. Surgery was the primary treatment for 98 % (213/218). Only 79 patients received hormonal adjuvant therapy, 58 % (46/79) Megace, 24 % (19/79) Letrozole, and 18 % (14/79) received other hormonal therapy. There was no significant difference in RFS (p = 0.159) and OS (p = 0.167) between patients receiving Megace versus Letrozole as adjuvant therapy. At first recurrence, patients given Megace had a similar RFS to those on Letrozole (p = 0.302), but a better OS (27 vs 10 months, p = 0.018). Negative status of estrogen, smooth muscle actin, and desmin were associated with lower RFS (p = 0.039, p = 0.002, and p = 0.015, respectively) and OS (p = 0.008, p = 0.012, and p = 0.013, respectively). Lymphovascular invasion was associated with lower RFS (p = 0.033), and negative status of progesterone was associated with lower OS (p = 0.003). There was no difference in oncologic outcomes between Megace and Letrozole in patients who received adjuvant therapy for LG-ESS. Megace may have potential survival advantage in recurrent disease. Further study is warranted to determine the most effective agents and their sequence in the treatment of LG-ESS. • Despite a high and late recurrence rate, LG-ESS shows a favorable prognosis. • Comparison of Megace and Letrozole for adjuvant therapy in LG-ESS reveals similar oncologic outcomes. • Megace demonstrates potential survival advantages in recurrent LG-ESS. [ABSTRACT FROM AUTHOR]

TheraCalTM LC is a resin-modified calcium silicate (Ca) resin (SMCR) that has proven to be an ideal material for dentin-pulp treatment due to its high rate of calcium formation. Biomaterials due to their Ca content tend to have an increase in their bioavailability, stimulating the formation of the dental bridge through the cells involved in the formation of mineralized tissues, promoting the differentiation of fibroblasts in odontoblasts and increasing the activity of the pyrophosphate enzyme responsible in dentin mineralization. The present study aimed to evaluate the inflammatory response to TheracalTM LC subcutaneously in Wistar rats. Six Wistar strain rats were used in which four subcutaneous surgical pockets were made. Each of these pockets was determined as a different quadrant, containing the following implants: 1 TheracalTM LC in polyethylene tube, 2 polyethylene tubes, 3 TheracalTM LC direct and 4 as control. The histological samples were processed, and different cell types were evaluated by light microscopy at 100X using the H&E and AT pH 2.3 stains. The results showed that there are significant differences in all cell types observed during the different exposure times. The differences in the cell types observed could be due to the exposure time to TheracalTM LC, to the polyethylene tube and to both. The evaluated tissue of the polyethylene tube implant and the polyethylene tube with TheracalTM LC present a greater inflammatory response, unlike in the tissue implanted with TheracalTM LC directly. [ABSTRACT FROM AUTHOR]

A new amino acid has been designed as a replacement for arginine (Arg, R) to protect the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) from proteases. This amino acid, denoted (Pro)hArg, is characterized by a proline skeleton bearing a specifically oriented guanidinium side chain. This residue combines the ability of Pro to induce turn-like conformations with the Arg side-chain functionality. The conformational profile of the CREKA analogue incorporating this Arg substitute has been investigated by a combination of simulated annealing and molecular dynamics. Comparison of the results with those previously obtained for the natural CREKA shows that (Pro)hArg significantly reduces the conformational flexibility of the peptide. Although some changes are observed in the backbone···backbone and side-chain···side-chain interactions, the modified peptide exhibits a strong tendency to accommodate turn conformations centered at the (Pro)hArg residue and the overall shape of the molecule in the lowest energy conformations characterized for the natural and the modified peptides exhibit a high degree of similarity. In particular, the turn orients the backbone such that the Arg, Glu, and Lys side chains face the same side of the molecule, which is considered important for bioactivity. These results suggest that replacement of Arg by (Pro)hArg in CREKA may be useful in providing resistance against proteolytic enzymes while retaining conformational features which are essential for tumor-homing activity. [ABSTRACT FROM AUTHOR]

Quantum mechanical calculations have been used to investigate how the incorporation of an amino group to the C β- or C γ-positions of the pyrrolidine ring affects the intrinsic conformational properties of the proline. Specifically, a conformational study of the N-acetyl- N′-methylamide derivatives of four isomers of aminoproline, which differ not only in the β- or γ-position of the substituent but also in its cis or trans relative disposition, has been performed. To further understand the role of the intramolecular hydrogen bonds between the backbone carbonyl groups and the amino side group, a conformational study was also performed on the corresponding four analogues of (dimethylamino)proline. In addition, the effects of solvation on aminoproline and (dimethylamino)proline dipeptides have been evaluated using a self-consistent reaction field model, and considering four different solvents (carbon tetrachloride, chloroform, methanol and water). Results indicate that the incorporation of the amino substituent into the pyrrolidine ring affects the conformational properties, with backbone···side chain intramolecular hydrogen bonds detected when it is incorporated in a cis relative disposition. In general, the incorporation of the amino side group tends to stabilize those structures where the peptide bond involving the pyrrolidine nitrogen is arranged in cis. The aminoproline isomer with the substituent attached to the C γ-position with a cis relative disposition is the most stable in the gas phase and in chloroform, methanol and water solutions. Replacement of the amino side group by the dimethylamino substituent produces significant changes in the potential energy surfaces of the four investigated (dimethylamino)proline-containing dipeptides. Thus, these changes affect not only the number of minima, which increases considerably, but also the backbone and pseudorotational preferences. In spite of these effects, comparison of the conformational preferences, i.e., the more favored conformers, calculated for different isomers of aminoproline and (dimethylamino)proline dipeptides showed a high degree of consistency for the two families of compounds. [ABSTRACT FROM AUTHOR]

The intrinsic conformational preferences of proline analogues having double bonds between carbon atoms in their rings have been investigated using quantum mechanical calculations at the B3LYP/6-31G(d,p) level. For this purpose, the potential energy surface of the N-acety-N‘-methylamide derivatives of three dehydroprolines (proline analogues unsaturated at ,; ,; and ,) and pyrrole (proline analogue with unsaturations at both , and ,) have been explored, and the results are compared with those obtained for the derivative of the nonmodified proline. We found that the double bonds affect the ring puckering and the geometric internal parameters, even though the backbone conformation was influenced the most. Results indicate that the formation of double bonds between carbon atoms in the pyrrolidine ring should be considered as an effective procedure to restrict the conformational flexibility of prolines. Interestingly, we also found that the N-acetyl-N‘-methylamide derivative of pyrrole shows a high probability of having a cis peptide bond preceding the proline analogue. [ABSTRACT FROM AUTHOR]

Objective: To review the available evidence on the early introduction of allergenic foods and the possible protection in the development of food allergy in later stages. Methods: An exploratory review of randomized clinical trials whose study population included infants less than 6 months of age at enrollment with or without a diagnosis of food allergy was conducted. For the purposes of this review, eggs, peanuts, and wheat were included as potentially allergenic foods. The following databases were consulted: Medline, EBSCO, OVID, Science Direct and JSTOR (Journal Storage), Scielo, LILACS, Redalyc and Imbiomed from August to December 2021. Results: 429 articles were identified, 412 were excluded, and the final analysis included 9 studies that met the inclusion criteria. Six trials correspond to allergy to eggs, two to peanuts and one to wheat. The age of introduction differs in all trials. The earliest exposure was at 3.5 months and the latest at 5.5 months. The reduction in the risk of developing food allergy occurred in children at risk of allergy. Adverse reactions were common, particularly with the introduction of egg. Conclusions: We found no evidence that early introduction (< 6 months of age) of allergenic foods reduces the risk of developing food allergy in infants without risk factors. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to determine survival outcomes following secondary (TRS-2) and tertiary (TRS-3) tumor reductive surgery in the management of recurrent adult-type granulosa cell tumors of the ovary (aGCT). Methods: This was a single-institution retrospective cohort study that included all women with a histologic diagnosis of aGCT who had at least one recurrence. Women aged <18 years at the time of their first visit were excluded. Following IRB approval, data regarding demographics, medical history, and treatment were obtained from the medical records. Descriptive statistics were used to compare variables by treatment modality. Progression-free survival after the first recurrence (PFS1) and second recurrence (PFS2) were estimated using the Kaplan-Meier method. Multivariable Cox regression models were used to adjust for covariates. A p-value of <0.05 was considered significant. Results: A total of 81 women met the inclusion criteria, of whom 70 (86.4%) had the resectable disease at the time of the first recurrence, based on the absence of a brain, bone, lung, or parenchymal liver metastases. The median age of initial diagnosis was 45 years (interquartile range (IQR): 36-53 years). The median age of the first recurrence was 53 years (IQR: 40-60 years). For treatment of a first recurrence, 66 women (81.5%) underwent TRS-2, and 50 (61.7%) received cytotoxic chemotherapy. Among women with resectable disease, the median PFS1 with TRS-2 was 36.5 months (95% CI: 27.7-47.0 months) and was 8.4 months (95% CI: 4.0-NR months) with the omission of TRS-2 (HR: 0.47, 95% CI: 0.26-0.83, p=0.009) (Figure 1A). Complete gross resection was achieved in 80% of cases. In a multivariable Cox regression analysis, women with the resectable disease who did not undergo TRS-2 had a higher risk of death or recurrence after adjusting for age at the time of recurrence and the use of cytotoxic chemotherapy (adjusted HR: 0.47, 95% CI: 025-0.88, p=0.018). A total of 53 women had a second documented recurrence, of which 45 (85.0%) had the resectable disease. For treatment of a second recurrence, 28 women (62.2%) underwent TRS-3, and 20 (44.4%) received cytotoxic chemotherapy. Among women with the resectable disease at the time of the second recurrence, the median PFS2 with TRS-3 was 25.2 months (95% CI: 14.5-63.3 months) versus 9.4 months (95% CI: 5.4 to 24.3) with the omission of TRS-3 (HR: 0.57, 95% CI: 0.35-0.91, p=0.018) (Figure 1B). In this cohort, 70% had a complete gross resection. The association of TRS-3 with improved PFS2 remained statistically significant after multivariable adjustment for age at the time of the second recurrence and the use of cytotoxic chemotherapy (adjusted HR: 0.56, 95% CI: 0.35-0.89, p=0.015). Conclusions: Among carefully selected women with resectable disease, treatment of recurrent aGCT with tumor reductive surgery is associated with improvement in progression-free survival at the time of both first and second recurrence. [Display omitted] [ABSTRACT FROM AUTHOR]

To evaluate the survival impact of adding definitive pelvic radiation therapy (RT) to chemotherapy among patients with stage IVB neuroendocrine cervical carcinoma (NECC). We retrospectively studied patients with FIGO 2018 stage IVB NECC diagnosed during 1998–2020 who received chemotherapy with or without definitive whole pelvic RT (concurrent or sequential). Demographic, oncologic, and treatment characteristics were summarized. Progression-free (PFS) and overall survival (OS) were plotted using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using Cox regression. The study included 71 patients. Median age was 43 years (range, 24–75). Fifty-nine patients (83%) had pure neuroendocrine histology, and 57 (80%) had pretreatment tumor size >4 cm. Fifty-six patients (79%) received chemotherapy alone with (n = 15) or without (n = 41) palliative pelvic RT, and 15 (21%) received chemotherapy and definitive pelvic RT (chemo+RT). Median follow-up time was 20.1 months (range, 11.3–170.3) for the chemo+RT group and 13.5 months (range, 0.9–73.6) for the chemotherapy-alone group. Median PFS was 10.3 months (95% CI, 7.5-∞) for the chemo+RT group vs 6.6 months (95% CI, 6.1–8.7) for the chemotherapy-alone group (p = 0.0097). At 24 months, the PFS rate was 24% for chemo+RT vs 7.8% for chemotherapy alone. Median OS was 20.3 months (95% CI, 18.5-∞) for the chemo+RT group vs 13.6 months (95% CI, 11.3–19.2) for the chemotherapy-alone group (p = 0.0013). At 24 months, the OS rate was 49.2% for chemo+RT vs 21.5% for chemotherapy alone. In a Cox regression model, definitive RT was associated with improved PFS (HR, 0.44; 95% CI, 0.23–0.83; p = 0.0119) and OS (HR, 0.31; 95% CI, 0.14–0.65; p = 0.0022). Addition of definitive pelvic RT to chemotherapy may improve survival in patients with stage IVB NECC. • In stage IVB neuroendocrine cervical carcinoma, definitive pelvic radiation therapy may confer a survival benefit • Complete response rates were higher after chemotherapy and definitive pelvic radiation therapy than after chemotherapy alone • Overall survival was longer in patients who received ≥5 cycles of chemotherapy, alone or with radiation therapy, vs <5 cycles [ABSTRACT FROM AUTHOR]

Recently, a potentially powerful strategy based on phage-display libraries has been presented to target tumors via homing peptides attached to nanoparticles. The Cys-Arg-Glu-Lys-Ala (CREKA) peptide sequence has been identified as a tumor-homing peptide that binds to clotted plasmas proteins present in tumor vessels and interstitium. The aim of this work consists of mapping the conformational profile of CREKA to identify the bioactive conformation. For this purpose, a conformational search procedure based on modified simulated annealing combined with molecular dynamics was applied to three systems that mimic the experimentally used conditions: (i) the free peptide; (ii) the peptide attached to a nanoparticle; and (iii) the peptide inserted in a phage display protein. In addition, the free peptide was simulated in an ionized aqueous solution environment, which mimics the ionic strength of the physiological medium. Accessible minima of all simulated systems reveal a multiple interaction pattern involving the ionized side chains of Arg, Glu, and Lys, which induces a β-turn motif in the backbone observed in all simulated CREKA systems. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to describe the anatomic patterns of recurrence, through multiple relapses, of adult-type granulosa cell tumors of the ovary (aGCTs). Methods: This was a retrospective cohort study that included women over the age of 18 with a histologic diagnosis of aGCT who were seen at one of two academic centers for the treatment of recurrent disease. Following IRB approval, demographic and clinical data were obtained from the medical records. Descriptive statistics were used to compare variables by treatment modality; p<0.05 was considered significant. Results: A total of 81 women met our study criteria and was included in the final cohort. The median age at initial diagnosis was 45 years (interquartile range [IQR]: 36-53 years). The median age at first recurrence was 53 years (IQR: 40-60 years). A total of 73 (90%) women had documented disease sites at first recurrence, which included the pelvis and pelvic lymph nodes (PLN) (37/73, 51%), paraaortic lymph nodes (PALN) (4/73, 6%), extra-pelvic abdomen or bowel (35/73, 48%) liver parenchyma (8/73, 11%), and lung (3/73, 4%). Of these patients, 58 (80%) received secondary tumor reductive surgery (TRS), while 45 (62%) received cytotoxic chemotherapy. A total of 48 (91%) women with a second recurrence had documented disease sites, of whom 30 (62%) received TRS and 21 (44%) received chemotherapy. Sites of disease in the second recurrence included pelvis/PLN (27/48, 56%), extra-pelvic abdomen or bowel (24/48, 50%), liver parenchyma (5/48, 10%), and/or lung (1/48, 2%). A total of 42 (79%) women with a third recurrence had documented sites of disease, of whom 21 (50%) received TRS and 14 (33%) received chemotherapy. Sites of disease include pelvis/PLN (21/42, 50%), extra-pelvic abdomen or bowel (17/42, 40%), liver parenchyma (4/42, 10%), and/or lung (2/42, 5%). A total of 31 (82%) women with a fourth recurrence had documented disease sites, with involvement of the pelvic cavity pelvis/PLN (14/31, 45%), extra-pelvic abdomen or bowel (14/31, 45%), liver parenchyma (5/31, 16%), and/or lung (1/31, 3%). Only nine women (29%) received TRS, and seven (23%) received chemotherapy for a fourth recurrence. Rates of TRS significantly decreased with each relapse (p<0.001). Rates of cytotoxic chemotherapy also decreased significantly (p<0.001). There were also no significant differences in the rate of locoregional disease (p=0.8) or distant metastases (p=0.9) between recurrences (Figure 1). No women in this cohort had documented central nervous system metastases. [Display omitted] Conclusions: Distant metastases of aGCT are rare, even after multiple lines of relapse, with the most recurrent disease confined to the abdomen and pelvis. Despite this, the frequency of TRS decreased through subsequent lines of treatment, suggesting that additional patient-related factors, such as performance status, may impact the decision to perform surgery for recurrent disease. [ABSTRACT FROM AUTHOR]