Project description:Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.
Project description:Leptomeningeal metastasis is an uncommon but serious complication in patients with advanced cancers. Leptomeningeal metastasis is diagnosed in approximately 5% of the patients, most commonly among patients with cancers of breast and lung, melanoma, and gastrointestinal malignancies. Treatment goal is to improve survival and quality of the patients. Use of targeted therapies and immunotherapy has led to improved survival of patients with non-small cell lung cancer (NSCLC). In this article, we review emerging data on use of mutation-specific agents and immunotherapy in the treatment of leptomeningeal metastasis among patients with NSCLC.
Project description:BackgroundThe problem of approximate string matching is important in many different areas such as computational biology, text processing and pattern recognition. A great effort has been made to design efficient algorithms addressing several variants of the problem, including comparison of two strings, approximate pattern identification in a string or calculation of the longest common subsequence that two strings share.ResultsWe designed an output sensitive algorithm solving the edit distance problem between two strings of lengths n and m respectively in time O((s - |n - m|).min(m, n, s) + m + n) and linear space, where s is the edit distance between the two strings. This worst-case time bound sets the quadratic factor of the algorithm independent of the longest string length and improves existing theoretical bounds for this problem. The implementation of our algorithm also excels in practice, especially in cases where the two strings compared differ significantly in length.ConclusionWe have provided the design, analysis and implementation of a new algorithm for calculating the edit distance of two strings with both theoretical and practical implications. Source code of our algorithm is available online.
Project description:The incidence of Clostridium difficile infection (CDI) has been rising in hospitals, long-term care facilities, and within the community. Cases have been more severe with more complications, deaths, and higher healthcare-associated costs. With the emergence of a hypervirulent strain of C. difficile and the increasing prevalence of community-acquired CDI among healthy patients without traditional risk factors, the epidemiology of C. difficile has been evolving. This changing epidemiology requires a change in management. Taking into account new risk factors for CDI and growing subpopulations of affected individuals, diagnostic, treatment, and prevention approaches need to be adjusted.
Project description:Glial-lineage malignancies (gliomas) recurrently mutate and/or delete the master regulators of apoptosis p53 and/or p16/CDKN2A, undermining apoptosis-intending (cytotoxic) treatments. By contrast to disrupted p53/p16, glioma cells are live-wired with the master transcription factor circuits that specify and drive glial lineage fates: these transcription factors activate early-glial and replication programs as expected, but fail in their other usual function of forcing onward glial lineage-maturation-late-glial genes have constitutively "closed" chromatin requiring chromatin-remodeling for activation-glioma-genesis disrupts several epigenetic components needed to perform this work, and simultaneously amplifies repressing epigenetic machinery instead. Pharmacologic inhibition of repressing epigenetic enzymes thus allows activation of late-glial genes and terminates glioma self-replication (self-replication = replication without lineage-maturation), independent of p53/p16/apoptosis. Lineage-specifying master transcription factors therefore contrast with p53/p16 in being enriched in self-replicating glioma cells, reveal a cause-effect relationship between aberrant epigenetic repression of late-lineage programs and malignant self-replication, and point to specific epigenetic targets for noncytotoxic glioma-therapy.
Project description:Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia that may be accompanied clinically by bleeding and reduced health-related quality of life (HRQoL). While corticosteroids, splenectomy, and various immunosuppressants (used off-label) have served as historical mainstays of ITP treatment, their use is associated with adverse effects and morbidity. Over the last 15 years, the advent of the thrombopoietin receptor agonists has revolutionized the management of chronic ITP with high response rates, durable responses, and minimal adverse effects in most patients. With four agents now FDA-approved to manage chronic ITP, there is a renewed emphasis on improving HRQoL and minimizing the toxicities associated with traditional therapies. Promising agents with diverse mechanisms of action, ranging from those targeting Bruton's Tyrosine Kinase to the neonatal Fc receptor, are currently under investigation. This review highlights recent landmark clinical trials which have made significant impacts on ITP management and ongoing drug development. In critically analyzing studies of relevance, we illustrate the changing paradigms of ITP management and how the field is advancing beyond traditional therapies.
Project description:The ability to learn abstract generalized structures of tasks is crucial for humans to adapt to changing environments and novel tasks. In a series of five experiments, we investigated this ability using a Rapid Instructed Task Learning paradigm (RITL) comprising short miniblocks, each involving two novel stimulus-response rules. Each miniblock included (a) instructions for the novel stimulus-response rules, (b) a NEXT phase involving a constant (familiar) intervening task (0-5 trials), (c) execution of the newly instructed rules (2 trials). The results show that including a NEXT phase (and hence, a prospective memory demand) led to relatively more robust abstract learning as indicated by increasingly faster responses with experiment progress. Multilevel modeling suggests that the prospective memory demand was just another aspect of the abstract task structure which has been learned.
Project description:Background: Primary jugular fossa meningiomas are one of the rarest subgroups of meningioma, with an estimated incidence of 0.7–4.3% of all skull base meningiomas. Indeed, only 145 cases of jugular foramen meningiomas have been reported in the literature to date. While meningiomas of this region are typically referred to as “jugular foramen meningiomas,” we make a distinction between meningiomas arising directly from the foramen itself, and those arising from the jugular tubercle. Jugular tubercle meningiomas, therefore, represent an even smaller subset of an already uncommon location for meningiomas. The jugular tubercle is the upper surface of the lateral parts of occipital bone presents an oval eminence, which overlies the hypoglossal canal and is sometimes crossed by an oblique groove for the glossopharyngeal, vagus, and accessory nerves. Only eight cases in the anterior foramen magnum lesions excised by a far lateral retrosigmoid approach have been described. The aim of this video article is to describe the surgical approach the senior author used to access lesion involving the jugular tubercle. Case Description: In this surgical video, we present a case of a 56-year-old female presented to our hospital with dizziness, headache, lower cranial nerves deficits, and lower limbs weakness. On exam, she was noted to have a left paraparesis, 9th, 10th, and 11th nerves palsies. An MRI scan demonstrated a mass in the region of the left jugular tubercle. Frozen section was suggestive of meningioma and our patient underwent a successful near total resection with no permanent neurologic sequelae. Conclusion: Jugular tubercle meningiomas are one of the rarest subgroups of meningioma. The described modified retrosigmoid approach provides outstanding access to the entire ventrolateral brainstem and cerebellopontine angle, with reduced approach related morbidity.
Project description:Hepatitis C virus (HCV) is a common cause of increased morbidity and mortality in kidney transplant patients. It is associated with posttransplant glomerulonephritis, chronic allograft nephropathy, and New Onset Diabetes after Transplant (NODAT). In the past, HCV was difficult to treat due to the presence of interferon alpha-based therapies that were difficult to tolerate and were associated with adverse side-effects, such as the risk of rejection. With the advent of oral directly acting antiviral therapies, the landscape for HCV and transplantation has changed. These agents are highly effective and well tolerated with minimal side-effects. Sustained viral response rates in excess of 90% are achieved with most current treatment regimens active against all HCV genotypes. These new agents may show an improvement in graft and patient survival while essentially eliminating the risk of acute rejection from the use of prior interferon-based HCV therapies. These agents may also result in an improvement in organ allocation for HCV donor/HCV recipient transplantation. This review is meant to discuss the epidemiology of HCV, the new oral direct-acting antiviral agents (DAAs) and future opportunities for research in the field of HCV related transplantation.