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Abstract Macropinocytosis has emerged as a scavenging pathway that cancer cells exploit to survive in a nutrient-deprived microenvironment. Tumor cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι, as regulators of macropinocytosis. In normal epithelial cells, aPKCs associate with the scaffold proteins Par3 and Par6 to regulate cell polarity, affecting several targets, including the Par1 kinases and we find that each of these proteins is required for macropinocytosis. Mechanistically, aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the Par3 relocation to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and aPKCs support PDAC growth in vivo. Our findings enhance our understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

Introduction: Anticipating which babies are in danger of experiencing poor outcomes during the perinatal period in uncomplicated appropriate for gestational age (AGA) pregnancies at term is difficult in obstetric practice. Cerebroplacental ratio (CPR) is emerging as a significant indicator of negative perinatal results. The current study sought to establish how effective CPR is in predicting negative perinatal outcomes in term uncomplicated AGA pregnancies. Materials and Methods: This study was a hospital-based prospective observational cohort study conducted at a single center. Patients were chosen depending on different criteria for inclusion and exclusion. A prenatal ultrasound with a color Doppler scan was carried out to calculate CPR. Patients were grouped according to their last CPR measurement before delivery into either normal CPR or pathological CPR categories. Doppler results did not impact clinical decisions and delivery followed institutional protocols. After childbirth, data on the outcome of the perinatal period were obtained from the patients’ medical records. Negative perinatal outcomes were assessed through the delivery method, APGAR score, perinatal morbidity, and perinatal mortality. These outcomes were correlated with CPR. Results: The research included 605 women, separated into normal and pathological CPR groups. Of these, 153 (25.3%) were classified in the pathological CPR category, whereas 452 (74.7%) exhibited normal CPR. In our study, there were 138 patients who experienced adverse perinatal outcomes in the pathological CPR group, whereas 44 patients had such outcomes in the normal CPR group. The diagnostic accuracy of pathological CPR to predict any negative perinatal result was 90.25%. Conclusions: CPR shows potential in detecting fetuses at risk in full-term uncomplicated AGA pregnancies.

A 62-year-old man presented with a slowly growing, painless lesion on his face. This eventually led to a progressive left-eye vision lesion, and the patient was subsequently diagnosed with advanced basal cell carcinoma (BCC). Of note, BCC involving cranial nerves is extremely rare, making this case unique and important to highlight. Standard treatment options for BCC involve surgery, radiation, or platinum-based chemotherapy. However, targeted therapies such as sonidegib and vismodegib – sonic hedgehog pathway inhibitors – have emerged that have been approved for treating BCC, as have anti-PD1 immunotherapies, such as cemiplimab, with their success likely based on the high tumor mutational burden seen in some of these tumors. Epidermal growth factor receptor (EGFR) inhibitors also serve a role in treating this condition as well. Molecular studies on metastatic/advanced BCC and other rare malignancies may inform treatment therapeutic decisions.

ABSTRACT: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that primarily causes the growth of tumors alongnerves. Additionally, the germline mutations involved in NF1 predispose patients to develop further malignancies. The mainstay initial treatment for these malignancies is surgical removal at diagnosis, although targeted therapies are under evaluation in the relapsed setting. We report a case of malignant peripheral nerve sheath tumor (MPNST), gastrointestinal stromal tumor (GIST), and pheochromocytoma in a patient with NF1 who presented with an infected right shoulder lesion that was confirmed to be spindle cell sarcoma via biopsy. She was treated with antibiotics; however, she rapidly deteriorated and opted for hospice care. NF1 germline mutations increase the risk of patients developing various types of cancer. Recent studies have shown that there is a rolefor using MEK inhibitors such as selumetinib for treating patients with NF1.

Primary splenic or hepatic angiosarcomas are ultra-rare and aggressive malignancies associated with poor prognosis. The mainstay treatments are surgical resection and chemotherapy. We report a case of angiosarcoma in a 50-year-old woman who presented with bruising, fatigue, ecchymosis, and hepatosplenomegaly. She was treated with the multi-kinase inhibitor sunitinib for 4 weeks before developing a splenic hemorrhage and succumbing. Recent studies have demonstrated the clinical benefit of immunotherapies in angiosarcomas. Additionally, sequencing techniques have showcased the diverse molecular aberrations involved in angiosarcomas, which offer opportunities for precision-matched targeted therapies such as inhibitors of the VEGF/VEGFR axis and PI3K/Akt/mTor pathway.

Authorship of peer-reviewed publications is important for academic rank, promotion, and national reputation. In pain medicine, limited information is available for authorship trends for women as compared with men. The objective of this study was to describe trends of female authorship data in the 5 pain journals with the highest impact factors over a 10-year period. We analyzed data for January, April, and October in 2009, 2014, and 2019. For each article, the following information was recorded: journal name, journal month, journal year, article title or article PMCID, total authors, total female authors, total male authors, total authors of unknown gender, presence or absence of a female first author, and presence or absence of a female last/senior author. Authorship for 924 articles was reviewed. When a man was senior author, women were first author on only 27.9% of articles (*P*\

The therapeutic landscape for lymphomas is quite diverse and includes active surveillance, chemotherapy, immunotherapy, radiation therapy, and even stem cell transplant. Advances in the field have led to the development of targeted therapies, agents that specifically act against a specific component within the critical molecular pathway involved in tumorigenesis. There are currently numerous targeted therapies that are currently Food and Drug Administration (FDA) approved to treat certain lymphoproliferative disorders. Of many, some of the targeted agents include rituximab, brentuximab vedotin, polatuzumab vedotin, nivolumab, pembrolizumab, mogamulizumab, vemurafenib, crizotinib, ibrutinib, cerdulatinib, idelalisib, copanlisib, venetoclax, tazemetostat, and chimeric antigen receptor (CAR) T-cells. Although these agents have shown strong efficacy in treating lymphoproliferative disorders, the complex biology of the tumors have allowed for the malignant cells to develop various mechanisms of resistance to the targeted therapies. Some of the mechanisms of resistance include downregulation of the target, antigen escape, increased PD-L1 expression and T-cell exhaustion, mutations altering the signaling pathway, and agent binding site mutations. In this manuscript, we discuss and highlight the mechanism of action of the above listed agents as well as the different mechanisms of resistance to these agents as seen in lymphoproliferative disorders.