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Purpose: This study aimed to compare the outcomes and toxicities between patients treated with image guided radiation therapy (IGRT) using fiducial markers and non-IGRT in intensity modulated radiation therapy (IMRT) for prostate cancer. Methods and Materials: In total, 518 patients with intermediate- and high-risk prostate cancer received IMRT with 78 Gy in 39 fractions after neoadjuvant androgen deprivation therapy for at least 3 months. Of these patients, 371 were in the non-IGRT group and 147 in the IGRT group, including the IGRT-A group using the same margins as the non-IGRT group and the IGRT-B group using reduced margins. The median follow-up periods for the non-IGRT, IGRT-A, and IGRT-B groups were 99 months, 88 months, and 63 months, respectively. Results: The 5-year biochemical recurrence-free survival rates in the non-IGRT, IGRT-A, and IGRT-B groups were 88%, 95%, and 98% (non-IGRT vs IGRT-A, P = .396; IGRT-A vs IGRT-B, P = .426), respectively. Those for intermediate- and high-risk patients were 94%, 93%, and 96% (non-IGRT vs IGRT-A, P = .916; IGRT-A vs IGRT-B, P = .646), respectively, and 87%, 96%, and 100% (non-IGRT vs IGRT-A, P = .500; IGRT-A vs IGRT-B, P = .483), respectively. For the non-IGRT and IGRT-A groups, the rates of acute grade ≥ 2 gastrointestinal toxicities and late grade ≥ 2 genitourinary toxicities were 17% and 7% (P = .019), respectively, and 28% and 16% (P = .028), respectively. In the IGRT-A and IGRT-B groups, the rates of acute grade ≥ 2 genitourinary toxicities were 45% and 21% (P = .003), respectively. All V60Gy = the volume at least received 60Gy and V70Gy = the volume at least received 70Gy values of the bladder and rectal walls in the IGRT-B group were smaller than those in the IGRT-A group. Conclusions: IGRT with fiducial markers results in lower acute and late toxicities compared with non-IGRT in IMRT for intermediate- and high-risk prostate cancer. Moreover, the toxicities are further decreased by reducing the margins in the treatment planning under IGRT. These processes do not decrease the biochemical recurrence-free survival rates.

Abstract Background Breast cancer-related leptomeningeal disease (BC-LMD) is a dire diagnosis for 5–8% of patients with breast cancer (BC). We conducted a retrospective review of BC-LMD patients diagnosed at Moffitt Cancer Center from 2011 to 2020, to determine the changing incidence of BC-LMD, factors which are associated with the progression of BC CNS metastasis to BC-LMD, and factors which are associated with OS for patients with BC-LMD. Methods Patients with BC and brain/spinal metastatic disease were identified. For those who eventually developed BC-LMD, we used Kaplan–Meier survival curve, log-rank test, univariable, and multivariate Cox proportional hazards regression model to identify factors affecting time from CNS metastasis to BC-LMD and OS. Results 128 cases of BC-LMD were identified. The proportion of BC-LMD to total BC patients was higher between 2016 and 2020 when compared to 2011–2015. Patients with HR+ or HER2 + BC experienced longer times between CNS metastasis and LMD than patients with triple-negative breast cancer (TNBC). Systemic therapy and whole-brain radiation therapy (WBRT) was associated with prolonged progression to LMD in all patients. Hormone therapy in patients with HR + BC were associated with a delayed BC-CNS metastasis to LMD progression. Lapatinib treatment was associated with a delayed progression to LMD in patients with HER2 + BC. Patients with TNBC-LMD had shorter OS compared to those with HR + and HER2 + BC-LMD. Systemic therapy, intrathecal (IT) therapy, and WBRT was associated with prolonged survival for all patients. Lapatinib and trastuzumab therapy was associated with improved OS in patients with HER2 + BC-LMD. Conclusions Increasing rates of BC-LMD provide treatment challenges and opportunities for clinical trials. Prospective trials testing lapatinib and/or similar tyrosine kinase inhibitors, IT therapies, and combination treatments are urgently needed.

Information regarding the endocrine regulation of oocyte maturation in cultured species is essential for the artificial seed production. To elucidate endocrine mechanisms that underlie oocyte maturation of the white-streaked grouper, Epinephelus ongus, a commercially important fish species, we collected and compared data linked to the ovaries of captive and wild white-streaked grouper specimens, and plasma steroids data were obtained using captive fish. This data allowed for a comparative analysis of the ovarian development of both groups; the comparison was necessary for the acquisition of physiological patterns universally representative of the species at hand. The dynamics of the gonadosomatic index (GSI) and oocyte development of both groups confirmed that vitellogenesis progressed toward the last quarter moon, final oocyte maturation began the day before the last quarter moon, and spawning occurred after the last quarter moon. These results indicate that the changes in ovarian development and GSI in wild and captive fish were synchronous, and that the endocrine changes observed in captive fish represent those that occur in wild fish. The changes in estradiol 17β (E2) levels in captive fish increased and decreased during the vitellogenic and final oocyte maturation phases, respectively. These dynamics were similar to those of GSI. We found that 17α, 20β-dihydroxy-4-pregnen-3-one (DHP) was consistently detected at concentrations higher than those of 17α, 20β-21-trihydroxy-4-pregnen-3-one (20β-S); this trend was constant across all stages of ovarian development. In contrast, 20β-S was detected at lower concentrations than DHP in all captive individuals, but at higher levels after the onset of final oocyte maturation. These results suggest that 20β-S and/or DHP may be maturation-inducing hormones (MIH) in this species. Our results also highlight the importance of integrative analyses of wild and captive individuals to comprehensively elucidate the endocrine regulation of cultured species of interest to improve aquaculture management practices.

Shahla Bari,1 David Boulware,2 Jiannong Li,2 Loretta Loftus,3 Aixa Soyano Muller,3 Zena Jameel,4 Hung Khong,3 Brian J Czerniecki,3 Ricardo LB Costa3 1Department of Hematology/Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 3Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 4Department of Anatomic and Clinical Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USACorrespondence: Ricardo LB Costa, Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA, Tel +813 745 3806, Fax +813 745 7287, Email ricardo.costa@moffitt.orgPurpose: Estrogen receptor-positive (ER+) breast cancer (BC) is a heterogeneous disease, and there is an ongoing debate regarding the optimal cut point for clinically relevant ER expression. We used a real-world database to assess the prognostic and predictive values of lower ER expression levels on treatment outcomes with endocrine therapy.Methods: We used a nationwide electronic health record database. Descriptive statistics were used to evaluate the association between ER expression, tumor characteristics, and treatment patterns among patients with early-stage BC. We used Kaplan–Meier survival curves to estimate recurrence-free survival (RFS) and overall survival (OS). We assessed associations between an alternative ER expression-level cut point and clinical outcomes.Results: Among 4697 patients with early-stage HER2-negative BC, 83 (2.04%) had ER+-low BC (ER expression, 1– 9.99%) and 36 (0.88%) had ER+-intermediate BC (10– 19.9%). ER+-low tumors were associated with higher tumor grade, larger size, and higher axillary tumor burden than ER+-high tumors (≥ 20% ER expression). African Americans had a higher prevalence of both triple-negative BC (TNBC) and ER+-low BC than ER+-high BC. Patients with ER+-low and ER+-intermediate tumors had survival outcomes similar to patients with TNBC and worse survival outcomes than patients with ER+-high tumors (P < 0.001). Tumors with < 20% ER expression were associated with worse outcomes.Conclusion: In our cohort, patients with BCs with ER expression levels < 20% had poor clinical outcomes similar to those of patients with TNBC.Keywords: breast cancer, estrogen receptor, low-positive, recurrence-free survival

Abstract Increasing attention has been paid to marine-derived biomolecules as sources of therapeutics for autoimmune diseases. Nagasaki Prefecture has many islands and is surrounded by seas, straits, gulfs, bays, and coves, giving it the second longest coastline in Japan after Hokkaido. We have collected more than 20,000 marine microbes and have been preparing an original marine microbial extract library, which contains small and mid-size biomolecules that may penetrate cell membranes and interfere with the intracellular protein–protein interaction involved in the development of autoinflammatory diseases such as familial Mediterranean fever. In addition, we have been developing an indoor shark farming system to prepare shark nanobodies that could be developed as potential therapeutic agents for autoimmune diseases. Sharks produce heavy-chain antibodies, called immunoglobulin new antigen receptors (IgNARs), consisting of one variable domain (VNAR) and five constant domains (CNAR); of these, VNAR can recognize a variety of foreign antigens. A VNAR single domain fragment, called a nanobody, can be expressed in Escherichia coli and has the properties of an ideal therapeutic candidate for autoimmune diseases. Shark nanobodies contain complementarity-determining regions that are formed through the somatic rearrangement of variable, diversity, and joining segments, with the segment end trimming and the N- and P-additions, as found in the variable domains of mammalian antibodies. The affinity and diversity of shark nanobodies are thus expected to be comparable to those of mammalian antibodies. In addition, shark nanobodies are physically robust and can be prepared inexpensively; as such, they may lead to the development of highly specific, stable, effective, and inexpensive biotherapeutics in the future. In this review, we first summarize the history of the development of conventional small molecule drugs and monoclonal antibody therapeutics for autoimmune diseases, and then introduce our drug discovery system at Nagasaki University, including the preparation of an original marine microbial extract library and the development of shark nanobodies.

Summary:. Here, we report the preparation of a nipple shield from an inexpensive and re-formable thermoplastic with metallic properties as well as its favorable outcomes when used for patients who had undergone nipple reconstruction. The nipple shield was prepared from a material made of a mixture of a thermoplastic resin and special aluminum pellets (aluminum content, 70%). Each patient wore the nipple shield for 3 months after nipple reconstruction. The material was re-softened for re-forming into an adequate shape as required during this 3-month period. All reconstructed nipples were securely protected, with no complications (eg, ulceration, wound dehiscence, and wound infections) during the 3-month period. Also, there were no skin complications such as contact dermatitis or cellulitis in the area where the nipple shield was in contact with the skin. None of the patients stopped using the nipple shield because it came off frequently, or was uncomfortable or painful to wear, and there were no cases in which the nipple shield had to be remade due to damage. The thermoplastic material used in this study appeared to be extremely useful as a nipple protection material because of its good breathability, attributed to its nonwoven form, its low thermal conductivity and resulting cooling effect attributed to its aluminum content, its suitability for rapid re-forming, and its washability.

This study aimed to compare toxicities, prostate volume and dosimetry, between patients who underwent intensity-modulated radiation therapy (IMRT) combined with ≥3 months of neoadjuvant androgen deprivation therapy (NADT) and those without NADT for prostate cancer. In total, 449 patients with intermediate- and high-risk prostate cancer received 78 Gy IMRT in 39 fractions, of which 129 were treated without any ADT (non-ADT group) and 320 with NADT ≥3 months (NADT group). Adverse events and dose-volume indices were compared between the two groups retrospectively. The NADT group had a lower rate of acute grade 2 gastrointestinal (GI) toxicities (17% vs 25%, P  = 0.063) and late grade 2 GI toxicities (P  = 0.055), including a significantly lower rate of late grade 2 rectal hemorrhage (P  = 0.033), compared with the non-ADT group. There were no cases of late grade 3 or higher GI toxicities. The average volume of the prostate in the NADT group was 38% smaller than that in the non-ADT group (43.7 vs 27.0 cm3, P  < 0.001). Bladder V40Gy and V50Gy, and rectum V40Gy, V50Gy, V60Gy and V70Gy were significantly smaller in the NADT group. In the NADT group, no significant difference was observed in adverse events or dosimetry between the subgroups with NADT ≥12 and <12 months. Acute and late rectal toxicities were reduced by NADT within ≥3 months in accordance with reduced prostate volume and improved rectal dosimetry. This suggests a merit of administering neoadjuvant ADT ≥3 months for reducing rectal toxicities. [ABSTRACT FROM AUTHOR]

(1) Fshβ and Lhβ showed stronger signals and higher transcript levels from 590 to 1050 dph than at earlier stages, implying their active involvement during primary oocyte development. (2) Fshβ and Lhβ at lower levels were detected during the phases of ovarian differentiation and oogonial proliferation. (3) E2 concentrations increased significantly at 174, 333, and 1435 dph, while T concentrations exhibited significant increases at 174 and 333 dph. These findings suggest potential correlations between serum E2 concentrations and the phases of oogonial proliferation and pre-vitellogenesis.

Legumes develop root nodules in association with compatible rhizobia to overcome nitrogen deficiency. Rhizobia enter the host legume, mainly through infection threads, and induce nodule primordium formation in the root cortex. Multiple transcription factors have been identified to be involved in the regulation of the establishment of root nodule symbiosis, including ERF Required for Nodulation1 (ERN1). ERN1 is involved in a transcription network with CYCLOPS and NODULE INCEPTION (NIN). Mutation of ERN1 often results in misshapen root hair tips, deficient infection thread formation, and immature root nodules. ERN1 directly activates the expression of ENOD11 in Medicago truncatula to assist cell wall remodeling and Epr3 in Lotus japonicus to distinguish rhizobial exopolysaccharide signals. However, aside from these two genes, it remains unclear which genes are regulated by LjERN1 or what role LjERN1 plays during root nodule symbiosis. Thus, we conducted RNA sequencing to compare the gene expression profiles of wild-type L. japonicus and Ljern1-6 mutants. In total, 234 differentially expressed genes were identified as candidate LjERN1 target genes. These genes were found to be associated with cell wall remodeling, signal transduction, phytohormone metabolism, and transcription regulation, suggesting that LjERN1 is involved in multiple processes during the early stages of the establishment of root nodule symbiosis. Many of these candidate genes including RINRK1 showed decreased expression levels in Ljnin-2 mutants based on a search of a public database, suggesting that LjERN1 and LjNIN coordinately regulate gene expression. Our data extend the current understanding of the pleiotropic role of LjERN1 in root nodule symbiosis.

Previous studies have shown the regulation of follicle-stimulating hormone (Fshβ) and luteinizing hormone (Lhβ) during early ovarian differentiation and development from 30 to 160 days post-hatching (dph) in the red-spotted grouper. This study investigates the immunohistochemical identification of Fshβ and Lhβ in the pituitary and gene expression of kiss1, kiss2, gpr54, gnrh1, fshβ, lhβ, fshr, and lhr in the brain, pituitary, and ovary from 160 to 420 dph in this species. Fshβ and Lhβ immunohistochemical signals were primarily detected in the proximal pars distalis area at each stage, with few Fshβ or Lhβ signals detected in the pars intermedia area at 160, 200, 270, 300, 330, 360, and 390 dph. The expression levels of fshβ at 160 dph and fshr at 200 dph were significantly elevated, suggesting that increased fshr expression may reflect increased fshβ levels. Therefore, Fshβ may be more active than Lhβ during oogonial proliferation and new oocyte generation. While expression levels of kiss1 and kiss2 at 270 and 390 dph, gpr54 at 360 dph, gnrh1 at 270 dph, and lhβ at 300 dph were significantly elevated, they were not significantly altered in most stages between 240 and 420 dph. However, a comparison of Fshβ and Lhβ signal intensity indicated that Fshβ signals from 270 to 420 dph and Lhβ signals from 240 to 420 dph were consistently higher than in earlier stages. These results suggest that Fshβ/Lhβ may be active during primary oocyte development in the red-spotted grouper.

Abstract Background Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression‐free survival (PFS) in patients with hormone receptor (HR)‐positive, HER2‐negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real‐world benefit of first‐line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors. Methods This study included HR‐positive, HER2‐negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression‐free survival (PFS) was determined using Kaplan–Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil‐to‐lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time‐dependent variable. Results In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93–NR). Median PFS for patients with bone‐only metastases (n = 54) was not reached (95% CI 18.21–NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33–33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71–0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97–1.18, p = 0.203). Conclusion The effectiveness of palbociclib and endocrine therapy in the treatment of HR‐positive, HER2‐negative mBC in the real‐world setting is similar to the efficacy reported in the PALOMA‐2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression.

Abstract Vertebrates usually exhibit gonochorism, whereby their sex is fixed throughout their lifetime. However, approximately 500 species (~ 2%) of extant teleost fishes change sex during their lifetime. Although phylogenetic and evolutionary ecological studies have recently revealed that the extant sequential hermaphroditism in teleost fish is derived from gonochorism, the evolution of this transsexual ability remains unclear. We revealed in a previous study that the tunica of the ovaries of several protogynous hermaphrodite groupers contain functional androgen-producing cells, which were previously unknown structures in the ovaries of gonochoristic fishes. Additionally, we demonstrated that these androgen-producing cells play critical roles in initiating female-to-male sex change in several grouper species. In the present study, we widened the investigation to include 7 genera and 18 species of groupers and revealed that representatives from most major clades of extant groupers commonly contain these androgen-producing cells, termed testicular-inducing steroidogenic (TIS) cells. Our findings suggest that groupers acquired TIS cells in the tunica of the gonads for successful sex change during their evolution. Thus, TIS cells trigger the evolution of sex change in groupers.

Clustering adalah jenismetode statistik yang dipakai untuk mengelompokan banyak data atau objek ke dalam beberapa kelompok (cluster), sehingga objek-objek yang berada dalam satu kelompok akan mempunyai kemiripan yang tinggi. Clustering K-Means merupakan metode pembentukan cluster berbasis data, dimana objek secara acak dalam cluster pertama yang terbentuk dijadikan sebagai titik tengah/titik pusat (centroid). K-means merupakan jenis cluster yang memiliki tingkat ketelitian dan efisiensi yang baik. Kelemahan dalam algoritma k-Means yaitu dalam menganalisa dan menentukan Nilai K dalam mengklaster data pada suatu dataset yang tidak optimal akan menghasilkan cluster yang buruk. Sum of Square Error (SSE) merupakan hasil penjumlahan dari seluruh jarak masing-masing data dengan titik pusat clusternya. Semakin kecil nilai SSE yang didapat, semakin seragam data yang ada didalam masing-masing cluster, semakin baik cluster yang dihasilkan. Penelitian ini melakukan analisis cluster dengan K-means untuk menghasilkan kelompok cluster serta perhitungan nilai Sum of Square Error untuk setiap data dengan nilai K yang berbeda. Proses perhitungan nilai K dalam mencari nilai SSE yang minimum sehingga dapat dilakukan perhitungan selisih nilai SSE dari setiap nilai K cluster. Hasil perhitungan selisih tersebut sebagai penentu jumlah K cluster yang optimal dengan tingkat akurasi yang lebih baik. Kata kunci: Clustering, K-Means, Sum of Square Error.

Host plants benefit from legume root nodule symbiosis with nitrogen-fixing bacteria under nitrogen-limiting conditions. In this interaction, the hosts must regulate nodule numbers and distribution patterns to control the degree of symbiosis and maintain root growth functions. The host response to symbiotic bacteria occurs discontinuously but repeatedly at the region behind the tip of the growing roots. Here, live-imaging and transcriptome analyses revealed oscillating host gene expression with approximately 6-hour intervals upon bacterial inoculation. Cytokinin response also exhibited a similar oscillation pattern. Cytokinin signaling is crucial to maintaining the periodicity, as observed in cytokinin receptor mutants displaying altered infection foci distribution. This periodic regulation influences the size of the root region responsive to bacteria, as well as the nodulation process progression. [ABSTRACT FROM AUTHOR]