PLCγ1 promotes phase separation of T cell signaling components.

The T cell receptor (TCR) pathway receives, processes, and amplifies the signal from pathogenic antigens to the activation of T cells. Although major components in this pathway have been identified, the knowledge on how individual components cooperate to effectively transduce signals remains limited. Phase separation emerges as a biophysical principle in organizing signaling molecules into liquid-like condensates. Here, we report that phospholipase Cγ1 (PLCγ1) promotes phase separation of LAT, a key adaptor protein in the TCR pathway. PLCγ1 directly cross-links LAT through its two SH2 domains. PLCγ1 also protects LAT from dephosphorylation by the phosphatase CD45 and promotes LAT-dependent ERK activation and SLP76 phosphorylation. Intriguingly, a nonmonotonic effect of PLCγ1 on LAT clustering was discovered. Computer simulations, based on patchy particles, revealed how the cluster size is regulated by protein compositions. Together, these results define a critical function of PLCγ1 in promoting phase separation of the LAT complex and TCR signal transduction

Durotaxis of Passive Nanoparticles on Elastic Membranes

The transport of macromolecules and nanoscopic particles to a target cellular site is a crucial aspect in many physiological processes. This directional motion is generally controlled via active mechanical and chemical processes. Here we show, by means of molecular dynamics simulations and an analytical theory, that completely passive nanoparticles can exhibit directional motion when embedded in nonuniform mechanical environments. Specifically, we study the motion of a passive nanoparticle adhering to a mechanically nonuniform elastic membrane. We observe a nonmonotonic affinity of the particle to the membrane as a function of the membrane’s rigidity, which results in the particle transport. This transport can be both up or down the rigidity gradient, depending on the absolute values of the rigidities that the gradient spans across. We conclude that rigidity gradients can be used to direct average motion of passive macromolecules and nanoparticles on deformable membranes, resulting in the preferential accumulation of the macromolecules in regions of certain mechanical properties

Cabergoline as an adjuvant to standard heart failure treatment in peripartum cardiomyopathy: a case report and review of the literature

Introduction: Peripartum cardiomyopathy (PPCM) is a rare and idiopathic form of dilated cardiomyopathy presenting late in pregnancy or early postpartum. Since the 16-kDa fragment of prolactin has been identified as a key factor in the pathophysiology of PPCM, prolactin inhibitors have been used as an adjuvant to standard heart failure treatment. Although bromocriptine is the current first choice, promising results have been reported with cabergoline, albeit scant. Case Presentation: We presented the case of a 41-year-old woman who received a diagnosis of PPCM one week after delivery and was successfully treated with cabergoline, finally experiencing a complete recovery. Conclusion: The case adds to the scant evidence supporting the use of cabergoline in PPCM patients. We argue that the favorable pharmacokinetic and metabolic profiles of this drug should prompt its consideration as a valid alternative prolactin inhibitor in these critical patients

Ovarian cancer metastasis to the breast: a case report and review of the literature

Although ovarian cancer often presents as a widespread disease, metastases to the breast and/or axillary lymph nodes are a very rare event, accounting for only 0.03-0.6% of all breast cancers. Its early recognition and accurate distinction from primary breast cancer are of crucial importance to choose an adequate systemic therapy over unnecessary surgeries. We presented the case of a 53-year-old woman who was diagnosed with breast metastases 2 years after the diagnosis of advanced primary serous ovarian cancer. The patient underwent primary cytoreductive surgery and platinum-based chemotherapy in combination with bevacizumab, followed by bevacizumab maintenance for 18 months. After 2 years of negative follow-ups, the disease unexpectedly spread to the left breast and axillary lymph nodes. No axillary lymph node dissection or breast surgery was performed. The patient received axillary radiotherapy and multiple chemotherapy lines: gemcitabine/cisplatin, liposomal doxorubicin, topotecan, olaparib/cediranib, paclitaxel, and cisplatin. Unfortunately, none of these treatments improved her prognosis and she died 3 years after the disease recurrence. Ovarian cancer metastasis to the breast reveals a disseminated disease with a poor prognosis. Currently, no valid treatment options are available as the disease shows multidrug chemoresistance. In the era of precision medicine, the characterization of genetic and molecular markers may play a role in offering new promising targeted therapies

Quantitative diffusion and perfusion MRI in the evaluation of endometrial cancer. Validation with histopathological parameters

Objectives: To investigate the role of quantitative Magnetic Resonance Imaging (MRI) in preoperative assessment of tumour aggressiveness in patients with endometrial cancer, correlating multiple parameters obtained from diffusion and dynamic contrast-enhanced (DCE) MR sequences with conventional histopathological prognostic factors and inflammatory tumour infiltrate.Methods: Forty-four patients with biopsy-proven endometrial cancer underwent preoperative MR imaging at 3T scanner, including DCE imaging, diffusion-weighted imaging (DWI) and intravoxel incoherent motion imaging (IVIM). Images were analysed on dedicated post-processing workstations and quantitative parameters were extracted: K-trans, K-ep, V-e and AUC from the DCE; ADC from DWI; diffusion D, pseudo diffusion D*, perfusion fraction f from IVIM and tumour volume from DWI. The following histopathological data were obtained after surgery: histological type, grading (G), lympho-vascular invasion (LVI), lymph node status, FIGO stage and inflammatory infiltrate.Results: ADC was significantly higher in endometrioid histology, G1-G2 (low grade), and stage IA. Significantly higher D* were found in endometrioid subptype, negative lymph nodes and stage IA. The absence of LVI is associated with higher f values. K-trans and V-e values were significantly higher in low grade. Higher D*, f and AUC occur with the presence of chronic inflammatory cells, D * was also able to distinguish chronic from mixed type of inflammation. Larger volume was significantly correlated with the presence of mixed-type inflammation, LVI, positive lymph nodes and stage >= IB.Conclusions: Quantitative biomarkers obtained from pre-operative DWI, IVIM and DCE-MR examination are an in vivo representation of the physiological and micro-structural characteristics of endometrial carcinoma allowing to obtain the fundamental parameters for stratification into Risk Classes.Advances in knowledge: Quantitative imaging biomarkers obtained from DWI, DCE and IVIM may improve preoperative prognostic stratification in patients with endometrial cancer leading to a more informed therapeutic choice

PARP inhibitors in endometrial cancer: current status and perspectives

Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endome-trial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors

Impact of covid-19 in gynecologic oncology: A nationwide italian survey of the sigo and mito groups

Objective: Coronavirus disease 2019 (COVID-19) has caused rapid and drastic changes in cancer management. The Italian Society of Gynecology and Obstetrics (SIGO), and the Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) promoted a national survey aiming to evaluate the impact of COVID-19 on clinical activity of gynecologist oncologists and to assess the implementation of containment measures against COVID-19 diffusion. Methods: The survey consisted of a self-administered, anonymous, online questionnaire. The survey was sent via email to all the members of the SIGO, and MITO groups on April 7, 2020, and was closed on April 20, 2020. Results: Overall, 604 participants completed the questionnaire with a response-rate of 70%. The results of this survey suggest that gynecologic oncology units had set a proactive approach to COVID-19 outbreak. Triage methods were adopted in order to minimize in-hospital diffusion of COVID-19. Only 38% of gynecologic surgeons were concerned about COVID-19 outbreak. Although 73% of the participants stated that COVID-19 has not significantly modified their everyday practice, 21% declared a decrease of the use of laparoscopy in favor of open surgery (19%). However, less than 50% of surgeons adopted specific protection against COVID-19. Additionally, responders suggested to delay cancer treatment (10%–15%), and to perform less radical surgical procedures (20%–25%) during COVID-19 pandemic. Conclusions: National guidelines should be implemented to further promote the safety of patients and health care providers. International cooperation is of paramount importance, as heavily affected nations can serve as an example to find out ways to safely preserve clinical activity during the COVID-19 outbreak

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks